Sulfonamide compounds having TRPM8 antagonistic activity

ABSTRACT

Sulfonamide compounds having TRPM8 antagonistic activity are provided. A sulfonamide compound of formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof: (I) wherein Ring A is bicyclic aromatic heterocycle comprised of (a) pyridine is condensed with benzene; or (b) pyridine is condensed with monocyclic aromatic heterocycle, and Ring A binds to a sulfonylamino moiety on a carbon atom adjacent to a nitrogen atom of the pyridine ring constituting Ring A, Ring B is (a) monocyclic or bicyclic aromatic hydrocarbon; (b) monocyclic or bicyclic alicyclic hydrocarbon; (c) monocyclic or bicyclic aromatic heterocycle; or (d) monocyclic or bicyclic non-aromatic heterocycle, Ring C is (a) benzene; or (b) monocyclic aromatic heterocycle, and other symbols are the same as defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase application based onPCT/JP2012/057412, filed Mar. 15, 2012, and claims the benefit of U.S.Provisional Application No. 61/453,396, filed Mar. 16, 2011, thecontents of both of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel sulfonamide compounds havingTRPM8 antagonistic activity which are useful as a medicament.

BACKGROUND ART

Transient receptor potential (TRP) channels are non-selective cationchannels that are activated by a variety of physical (e.g., temperature,osmolarity, mechanical) and chemical stimuli. A subset of the TRPchannel superfamily is thermoresponsive, each channel being activatedover a discrete temperature range, cumulatively spanning from noxiouscold to noxious heat. TRP melastatin 8 (TRPM8) belongs to the melastatinsubgroup of the TRP channel superfamily. TRPM8 is sensitive to coldtemperature and menthol, and therefore also called as cold mentholreceptor-1 (CMR-1) (e.g., Nonpatent Document 1). TRPM8 is known to bestimulated by cool to cold temperatures (8 to 28° C.) as well as bychemical substances such as menthol and icilin.

TRPM8 is located on primary nociceptive neurons (A-δ and C-fibers) andis also modulated by inflammation-mediated second messenger signals(e.g., Nonpatent Document 2 and 3). The location of TRPM8 on both A-δand C-fibers may provide a basis for abnormal cold sensitivity inpathologic conditions wherein these neurons are altered, resulting inpain, often of a burning nature. TRPM8 immunostaining in primaryafferents was increased in rats with chronic constriction injury (CCI),a neuropathic pain model manifesting cold allodynia in hindlimbs (e.g.,Nonpatent Document 4). The expression of TRPM8 in primary afferents wasincreased in oxaliplatin-induced cold allodynia model in mice (e.g.,Nonpatent Document 5).

Cold intolerance and paradoxical burning sensations induced by chemicalsubstances or thermal cooling closely parallel symptoms seen in a widerange of clinical disorders and thus provide a strong rationale for thedevelopment on TRPM8 modulators as novel antihyperalgesic orantiallodynic agents. TRPM8 is also known to be expressed in the brain,lung, bladder, gastrointestinal tract, blood vessels, prostate andimmune cells, thereby providing the possibility for therapeuticmodulation in a wide range of maladies.

N-Benzothiopheneylsulfonamide compounds (e.g., Patent Document 1),N-benzimidazolylsulfonamide compounds (e.g., Patent Document 2),N-phenylsulfonamide compounds, N-pyridylsulfonamide compounds (e.g.,Patent Document 3), etc. have been known as a TRPM8 modulator. However,it has never been reported that a compound wherein the compound has abicyclic aromatic heterocycle comprised of pyridine condensed withbenzene or of pyridine condensed with monocyclic aromatic heterocycleand the bicyclic aromatic heterocyle binds to a sulfonylamino moiety hasTRPM8 antagonistic activity.

[Patent document 1] WO 2009/012430 pamphlet

[Patent document 2] WO 2010/144680 pamphlet

[Patent document 3] WO 2010/125831 pamphlet

[Nonpatent document 1] D. D. McKemy, and other two persons,“Identification of a cold receptor reveals a general role for TRPchannels in thermosensation”, Nature, 2002, Vol. 416, No. 6876, p. 52-58

[Nonpatent document 2] J. Abe, and other four persons, “Ca²⁺-dependentPKC activation mediates menthol-induced desensitization of transientreceptor potential M8”, Neuroscience Letters, 2006, Vol. 397, No. 1-2,p. 140-144

[Nonpatent document 3] L. S. Premkumar, and other four persons,“Downregulation of Transient Receptor Potential Melastatin 8 by ProteinKinase C-Mediated Dephosphorylation”, The Journal of Neuroscience, 2005,Vol. 25, No. 49, p. 11322-11329

[Nonpatent document 4] H. Xing, and other four persons, “TRPM8 Mechanismof Cold Allodynia after Chronic Nerve Injury”, The Journal ofNeuroscience, 2007, Vol. 27, No. 50, p. 13680-13690

[Nonpatent document 5] P. Gauchan, and other three persons, “Involvementof increased expression of transient receptor potential melastatin 8 inoxaliplatin-induced cold allodynia in mice”, Neuroscience Letters, 2009,Vol. 458, No. 2, p. 93-95

SUMMARY OF INVENTION Problems to be Solved by the Invention

The purpose of the present invention is to provide novel sulfonamidecompounds having TRPM8 antagonistic activity which are useful as amedicament.

Means of Solving the Problems

The present invention is directed to a compound of formula (I):

wherein Ring A is bicyclic aromatic heterocycle comprised of (a)pyridine condensed with benzene; or (b) pyridine condensed withmonocyclic aromatic heterocycle, and Ring A binds to a sulfonylaminomoiety on a carbon atom adjacent to a nitrogen atom of the pyridine ringconstituting Ring A,

Ring B is (a) monocyclic or bicyclic aromatic hydrocarbon; (b)monocyclic or bicyclic alicyclic hydrocarbon; (c) monocyclic or bicyclicaromatic heterocycle; or (d) monocyclic or bicyclic non-aromaticheterocycle,

Ring C is (a) benzene; or (b) monocyclic aromatic heterocycle,

R¹ is (a) hydrogen; (b) optionally substituted alkyl; (c) optionallysubstituted cycloalkyl; (d) optionally substituted alkoxy; (e)optionally substituted phenyl; (f) halogen; or (g) nitrile,

R^(2a), R^(2b), R^(2c) and R^(2d) are each independently (a) hydrogen;(b) optionally substituted alkyl; (c) optionally substituted cycloalkyl;(d) optionally substituted alkoxy; (e) optionally substituted phenyl;(f) optionally substituted monocyclic aromatic heterocyclic group; (g)optionally substituted monocyclic non-aromatic heterocyclic group; (h)halogen; or (i) nitrile,

R^(3a), R^(3b), R^(3c) and R^(3d) are each independently (a) hydrogen;(b) optionally substituted alkyl; (c) optionally substituted cycloalkyl;(d) optionally substituted alkoxy; (e) optionally substitutedcycloalkoxy; (f) optionally substituted phenyl; (g) optionallysubstituted monocyclic aromatic heterocyclic group; (h) optionallysubstituted monocyclic non-aromatic heterocyclic group; (i) optionallysubstituted phenoxy; (j) halogen; or (k) hydroxy, or two substituentgroups selected from R^(3a), R^(3b), R^(3c) and R^(3d) combine eachother to form oxo,

R⁵ and R⁶ are each independently (a) hydrogen; (b) alkyl; (c)halogenoalkyl; (d) cycloalkyl; or (e) halogenocycloalkyl, or R⁵ and R⁶combine each other at their terminals together with the adjacent carbonatom to form monocyclic alicyclic hydrocarbon,

n is 0, 1 or 2,

X is carboxy, alkoxycarbonyl, hydroxyalkyl, optionally substitutedaminocarbonyl, or optionally substituted alkanoyl; or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof.

Effect of the Invention

A compound of formula (I) shows excellent inhibitory effects on behaviorinduced by TRPM8 agonists as well as excellent TRPM8 antagonisticactivity. Accordingly, a compound of formula (I) is useful as amedicament for prevention and treatment of various diseases involvingTRPM8 (e.g., chronic pain such as neuropathic pain (preferably,neuropathic pain caused by cold allodynia or diabetic neuropathy)).

DESCRIPTION OF EMBODIMENTS

Each definition of each term used herein is as follows.

The term “alkyl” refers to straight or branched-chain saturatedhydrocarbon chain with 1 to 6 carbons, and includes methyl, ethyl,propyl, isopropyl, butyl, t-butyl, isobutyl, and various branched-chainisomers thereof, preferably straight or branched-chain saturatedhydrocarbon chain with 1 to 4 carbons.

The term “alkenyl” refers to straight or branched-chain unsaturatedhydrocarbon chain with 2 to 6 carbons containing one carbon-carbondouble bond, and includes vinyl, propenyl, butenyl, and variousbranched-chain isomers thereof, preferably straight or branched-chainunsaturated hydrocarbon chain with 2 to 4 carbons.

The term “cycloalkyl” refers to alicyclic saturated hydrocarbon with 3to 7 carbons, and includes cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, preferably alicyclic saturated hydrocarbon with 3 to 6carbons.

The term “cycloalkenyl” refers to alicyclic unsaturated hydrocarbon with3 to 7 carbons containing one carbon-carbon double bond, and includescyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, preferablyalicyclic unsaturated hydrocarbon with 3 to 6 carbons.

The term “halogen” or “halogeno” refers to fluorine, chlorine, bromineand iodine, preferably chlorine and fluorine.

The term “alkoxy” refers to a group wherein oxygen atom binds to thestraight or branched-chain alkyl with 1 to 6 carbons, and includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, andvarious branched-chain isomers thereof, preferably a group whereinoxygen atom binds to straight or branched-chain saturated hydrocarbonwith 1 to 4 carbons.

The term “cycloalkoxy” refers to a group wherein oxygen atom binds tothe cycloalkyl with 3 to 7 carbons, and includes cyclopropoxy,cyclobutoxy, cyclopentoxy or cyclohexoxy, preferably a group whereinoxygen atom binds to alicyclic saturated hydrocarbon with 3 to 6carbons.

The term “alkanoyl” refers to a group wherein the alkyl binds tocarbonyl, and includes acetyl, propanoyl, butyryl, pentanoyl and variousbranched-chain isomers thereof, preferably a group wherein straight orbranched-chain saturated hydrocarbon chain with 1 to 4 carbons binds tocarbonyl.

The terms “halogenoalkyl”, “halogenoalkoxy” and “halogenocycloalkyl”refer to the alkyl, alkoxy and cycloalkyl which are substituted by 1 to7 halogen atoms, respectively.

The term “monocyclic or bicyclic aromatic hydrocarbon” refers tomonocyclic or bicyclic aromatic hydrocarbon with 6 to 11 carbons as aring atom, and includes monocyclic aromatic hydrocarbon such as benzene;and bicyclic aromatic hydrocarbon with 9 to 11 carbons as a ring atomsuch as naphthalene, tetrahydronaphthalene, indene, indane or azulene.

The term “monocyclic alicyclic hydrocarbon” refers to monocyclicalicyclic hydrocarbon with 3 to 7 carbons as a ring atom, and includescyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane orcyclohexene, preferably monocyclic alicyclic hydrocarbon with 3 to 6carbons as a ring atom.

The term “monocyclic or bicyclic alicyclic hydrocarbon” refers tomonocyclic or bicyclic alicyclic hydrocarbon with 3 to 12 carbons as aring atom, and includes monocyclic alicyclic hydrocarbon with 3 to 7carbons as a ring atom such as cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane or cyclohexene; bicyclic alicyclic hydrocarbonwith 8 to 12 carbons as a ring atom such as bicyclooctane,bicyclononane, bicyclononene, bicyclodecane, bicyclodecene,spiro-octane, spiro-nonane, spiro-decane or spiro-undecane.

The term “monocyclic aromatic heterocycle” refers to 5 to 6-memberedmonocyclic aromatic heterocycle containing carbon atoms and 1 to 4heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,and includes pyrrole, furan, thiophene, pyrazole, imidazole, oxazole,isooxazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine orpyridazine.

The term “monocyclic or bicyclic aromatic heterocycle” refers to 5 to11-membered monocyclic or bicyclic aromatic heterocycle containingcarbon atoms and 1 to 4 heteroatoms selected from oxygen atom, sulfuratom and nitrogen atom, and includes 5 to 6-membered monocyclic aromaticheterocycle such as pyrrole, furan, thiophene, pyrazole, imidazole,oxazole, isooxazole, thiazole, isothiazole, thiadiazole, pyridine,pyrimidine or pyridazine; 8 to 11-membered bicyclic aromatic heterocyclesuch as indole, indoline, isoindoline, indazole, benzofuran,dihydrobenzofuran, dihydroisobenzofuran, benzothiophene,dihydrobenzothiophene, dihydroisobenzothiophene, benzooxazole,dihydrobenzooxazole, benzothiazole, dihydrobenzothiazole, quinoline,tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline,naphthyridine, tetrahydronaphthyridine, quinoxaline,tetrahydroquinoxaline or quinazoline.

The term “monocyclic or bicyclic non-aromatic heterocycle” refers to 4to 12-membered monocyclic or bicyclic non-aromatic heterocyclecontaining carbon atoms and 1 to 4 heteroatoms selected from oxygenatom, sulfur atom and nitrogen atom, and includes 4 to 7-memberedmonocyclic non-aromatic heterocycle such as pyrrolidine, piperidine,tetrahydrofuran, tetrahydrothiophene, dihydroisooxazole and morpholine;8 to 12-membered bicyclic non-aromatic heterocycle such asoctahydroindoline, octahydrobenzofuran, octahydrobenzothiophene,decahydroquinoline, decahydroisoquinoline, oxaaza-spiro-nonene,oxaaza-spiro-decene, oxaaza-spiro-undecene.

The term “monocyclic aromatic heterocyclic group” refers to 5 to6-membered monocyclic aromatic heterocyclic group containing carbonatoms and 1 to 4 heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom, and includes pyrrolyl, furyl, thienyl, pyrazolyl,imidazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyrimidyl or pyridazyl.

The term “monocyclic non-aromatic heterocyclic group” refers to 4 to7-membered monocyclic non-aromatic heterocyclic group containing carbonatoms and 1 to 4 heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom, and includes pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydrothienyl, dihydroisooxazolyl and morpholyl.

Each definition of each symbol in a compound of formula (I) is explainedin detail as follows.

The monocyclic aromatic heterocycle in the “bicyclic aromaticheterocycle comprised of pyridine condensed with monocyclic aromaticheterocycle” of Ring A is preferably pyrrole, thiophene or pyridine.

Ring A is preferably bicyclic aromatic heterocycle comprised of (a)pyridine condensed with benzene; (b) pyridine condensed with pyrrole;(c) pyridine condensed with thiophene; or (d) pyridine condensed withpyridine, particularly bicyclic aromatic heterocycle comprised ofpyridine condensed with benzene, specifically quinoline (particularly,quinolin-2-yl) or isoquinoline (particularly, isoquinolin-3-yl).

The “monocyclic or bicyclic aromatic hydrocarbon” of Ring B ispreferably benzene, naphthalene, tetrahydronaphthalene, or indane.

The “monocyclic or bicyclic alicyclic hydrocarbon” of Ring B ispreferably cyclopentane or cyclohexane.

The “monocyclic or bicyclic aromatic heterocycle” of Ring B ispreferably thiophene, pyridine, pyrimidine, indole, indazole,dihydrobenzofuran, dihydroisobenzofuran, benzothiophene, benzooxazole,benzothiazole, quinoline or isoquinoline.

The “monocyclic or bicyclic non-aromatic heterocycle” of Ring B ispreferably piperidine or oxaaza-spiro-decene.

Ring B is preferably (a) monocyclic or bicyclic aromatic hydrocarbon; or(b) monocyclic or bicyclic aromatic heterocycle, specifically benzene,naphthalene, tetrahydronaphthalene, indane, thiophene, pyridine,pyrimidine, indole, indazole, dihydrobenzofuran, dihydroisobenzofuran,benzothiophene, benzooxazole, benzothiazole, quinoline or isoquinoline,more preferably benzene, naphthalene, tetrahydronaphthalene, indane,thiophene, pyridine, indole or benzothiophene, particularly benzene,naphthalene (particularly, naphthalen-2-yl), tetrahydronaphthalene(particularly, 1,2,3,4-tetrahydronaphthalen-6-yl), indane (particularly,indan-1-yl or indan-5-yl), pyridine (particularly, pyridin-2-yl) orbenzothiophene (particularly, benzothiophen-2-yl).

The “monocyclic aromatic heterocycle” of Ring C is preferably thiopheneor pyridine.

Ring C is preferably benzene, thiophene or pyridine, particularlybenzene.

The number of the substituents in the “optionally substituted alkyl” ofR¹ may be one or more (for example, 1 to 7), and the substituents may bethe same or different. As for such substituents, cycloalkyl, alkoxy,halogen, oxo and hydroxy can be mentioned for example.

The number of the substituents in the “optionally substitutedcycloalkyl” of R¹ may be one or more (for example, 1 to 7), and thesubstituents may be the same or different. As for such substituents,alkyl, alkoxy and halogen can be mentioned for example.

The number of the substituents in the “optionally substituted alkoxy” ofR¹ may be one or more (for example, 1 to 7), and the substituents may bethe same or different. As for such substituents, cycloalkyl, alkoxy,halogen and hydroxy can be mentioned for example.

The number of the substituents in the “optionally substituted phenyl” ofR¹ may be one or more (for example, 1 to 3), and the substituents may bethe same or different. As for such substituents, alkyl, halogenoalkyl,cycloalkyl, halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen canbe mentioned for example.

R¹ is preferably (a) hydrogen; (b) optionally substituted alkyl; (c)optionally substituted cycloalkyl; (d) optionally substituted alkoxy; or(e) halogen. More preferable one is (a) hydrogen; (b) C₁-C₆ alkyl whichmay be optionally substituted by 1 to 7 groups selected from halogen,oxo and hydroxy; (c) C₃-C₇ cycloalkyl; (d) C₁-C₆ alkoxy; or (e) halogen,and specifically, hydrogen, methyl, trifluoromethyl, ethyl, oxoethyl,hydroxyethyl, isopropyl, cyclopropyl, methoxy, chloro or bromo ispreferable. Particularly, (a) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 halogens; (b) C₃-C₇ cycloalkyl; (c) C₁-C₆ alkoxy;or (d) halogen is preferable, and specifically, methyl, trifluoromethyl,isopropyl, cyclopropyl or methoxy is preferable. More preferable one ismethyl, trifluoromethyl or cyclopropyl.

The number of the substituents in the “optionally substituted alkyl” ofR^(2a), R^(2b), R^(2c) or R^(2d) may be each one or more (for example, 1to 7), and the substituents may be the same or different. As for suchsubstituents, alkoxy, cycloalkyl, halogen, oxo and hydroxy can bementioned for example.

The number of the substituents in the “optionally substitutedcycloalkyl” of R^(2a), R^(2b), R^(2c) or R^(2d) may be each one or more(for example, 1 to 7), and the substituents may be the same ordifferent. As for such substituents, alkyl, alkoxy and halogen can bementioned for example.

The number of the substituents in the “optionally substituted alkoxy” ofR^(2a), R^(2b), R^(2c) or R^(2d) may be each one or more (for example, 1to 7), and the substituents may be the same or different. As for suchsubstituents, alkoxy, cycloalkyl and halogen can be mentioned forexample.

The number of the substituents in the “optionally substituted phenyl” ofR^(2a), R^(2d) may be each one or more (for example, 1 to 3), and thesubstituents may be the same or different. As for such substituents,alkyl, halogenoalkyl, cycloalkyl, halogenocycloalkyl, alkoxy,halogenoalkoxy and halogen can be mentioned for example.

The number of the substituents in the “optionally substituted monocyclicaromatic heterocyclic group” of R^(2a), R^(2b), R^(2c) or R^(2d) may beeach one or more (for example, 1 to 3), and the substituents may be thesame or different. As for such substituents, alkyl, halogenoalkyl,cycloalkyl, halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen canbe mentioned for example.

The number of the substituents in the “optionally substituted monocyclicnon-aromatic heterocyclic group” of R^(2a), R^(2b), R^(2c) or R^(2d) maybe each one or more (for example, 1 to 3), and the substituents may bethe same or different. As for such substituents, alkyl, halogenoalkyl,cycloalkyl, halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen canbe mentioned for example.

R^(2a), R^(2b) and R^(2c) are each independently and preferably (a)hydrogen; (b) optionally substituted alkyl; (c) optionally substitutedcycloalkyl; or (d) halogen. More preferable one is (a) hydrogen; (b)C₁-C₆ alkyl; (c) C₃-C₇ cycloalkyl; or (d) halogen, and specifically,hydrogen, methyl, cyclopropyl or chlorine is preferable. Particularly,hydrogen is preferable.

R^(2d) is preferably (a) hydrogen; (b) optionally substituted alkyl; (c)optionally substituted cycloalkyl; (d) optionally substituted alkoxy;(e) optionally substituted phenyl; (f) optionally substituted monocyclicaromatic heterocyclic group; (g) optionally substituted monocyclicnon-aromatic heterocyclic group; or (h) halogen. More preferable one is(a) hydrogen; (b) C₁-C₆ alkyl which may be optionally substituted by 1to 7 groups selected from C₁-C₆ alkoxy, halogen and hydroxy; (c) C₃-C₇cycloalkyl; (d) C₁-C₆ alkoxy; (e) phenyl; (f) 5 to 6-membered monocyclicaromatic heterocyclic group; (g) monocyclic non-aromatic heterocyclicgroup; or (h) halogen, and specifically, hydrogen, methyl,trifluoromethyl, methoxymethyl, ethyl, hydroxyethyl, propyl, isopropyl,cyclopropyl, cyclopentyl, methoxy, ethoxy, isopropoxy, phenyl, pyridyl,pyrrolidyl, fluorine, chlorine or bromine is preferable. Particularly,(a) hydrogen; (b) C₁-C₆ alkyl; (c) C₃-C₇ cycloalkyl; or (d) C₁-C₆ alkoxyis preferable, and specifically, hydrogen, methyl, ethyl, isopropyl,cyclopropyl, cyclopentyl, methoxy or ethoxy is preferable. Morepreferable one is hydrogen, isopropyl or cyclopropyl.

The number of the substituents in the “optionally substituted alkyl” ofR^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more (for example, 1to 7), and the substituents may be the same or different. As for suchsubstituents, cycloalkyl, halogenocycloalkyl (in which the cycloalkyland halogenocycloalkyl may be each independently and optionallysubstituted by 1 to 3 groups selected from alkyl and halogenoalkyl),alkoxy, halogenoalkoxy, phenyl, monocyclic aromatic heterocyclic group,monocyclic non-aromatic heterocyclic group (in which the phenyl,aromatic heterocyclic group and non-aromatic heterocyclic group may beeach independently and optionally substituted by 1 to 3 groups selectedfrom alkyl, halogenoalkyl, cycloalkyl, halogenocycloalkyl, alkoxy,halogenoalkoxy and halogen), halogen, oxo and hydroxy can be mentionedfor example.

The number of the substituents in the “optionally substitutedcycloalkyl” of R^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more(for example, 1 to 7), and the substituents may be the same ordifferent. As for such substituents, alkyl, halogenoalkyl, alkoxy,halogenoalkoxy, halogen and hydroxy can be mentioned for example.

The number of the substituents in the “optionally substituted alkoxy” ofR^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more (for example, 1to 7), and the substituents may be the same or different. As for suchsubstituents, cycloalkyl, halogenocycloalkyl (in which the cycloalkyland halogenocycloalkyl may be each independently and optionallysubstituted by 1 to 3 groups selected from alkyl and halogenoalkyl),alkoxy, halogenoalkoxy, phenyl, monocyclic aromatic heterocyclic group,monocyclic non-aromatic heterocyclic group (in which the phenyl,aromatic heterocyclic group and non-aromatic heterocyclic group may beeach independently and optionally substituted by 1 to 3 groups selectedfrom alkyl, halogenoalkyl, cycloalkyl, halogenocycloalkyl, alkoxy,halogenoalkoxy and halogen), halogen and hydroxy can be mentioned forexample.

The number of the substituents in the “optionally substitutedcycloalkoxy” of R^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more(for example, 1 to 7), and the substituents may be the same ordifferent. As for such substituents, alkyl, halogenoalkyl, alkoxy,halogenoalkoxy, halogen and hydroxy can be mentioned for example.

The number of the substituents in the “optionally substituted phenyl” ofR^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more (for example, 1to 3), and the substituents may be the same or different. As for suchsubstituents, alkyl, halogenoalkyl, cycloalkyl, halogenocycloalkyl,alkoxy, halogenoalkoxy and halogen can be mentioned for example.

The number of the substituents in the “optionally substituted monocyclicaromatic heterocyclic group” of R^(3a), R^(3b), R^(3c) or R^(3d) may beeach one or more (for example, 1 to 3), and the substituents may be thesame or different. As for such substituents, alkyl, halogenoalkyl,cycloalkyl, halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen canbe mentioned for example.

The number of the substituents in the “optionally substituted monocyclicnon-aromatic heterocyclic group” of R^(3a), R^(3b), R^(3c) or R^(3d) maybe each one or more (for example, 1 to 3), and the substituents may bethe same or different. As for such substituents, alkyl, halogenoalkyl,cycloalkyl, halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen canbe mentioned for example.

The number of the substituents in the “optionally substituted phenoxy”of R^(3a), R^(3b), R^(3c) or R^(3d) may be each one or more (forexample, 1 to 3), and the substituents may be the same or different. Asfor such substituents, alkyl, halogenoalkyl, cycloalkyl,halogenocycloalkyl, alkoxy, halogenoalkoxy and halogen can be mentionedfor example.

R^(3a), R^(3b), R^(3c) and R^(3d) are each independently and preferably(a) hydrogen; (b) optionally substituted alkyl; (c) optionallysubstituted cycloalkyl; (d) optionally substituted alkoxy; (e)optionally substituted cycloalkoxy; (f) optionally substituted phenyl;(g) optionally substituted monocyclic aromatic heterocyclic group; (h)optionally substituted phenoxy; (i) halogen; or (j) hydroxy. Morepreferable one is (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl (in whichthe cycloalkyl may be optionally substituted by 1 to 3 groups selectedfrom C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆halogenoalkoxy, halogen and hydroxy; (c) C₃-C₇ cycloalkyl which may beoptionally substituted by 1 to 7 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl and halogen; (d) C₁-C₆ alkoxy which may be optionallysubstituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy and halogen; (e) C₃-C₇ cycloalkoxy; (f)phenyl which may be optionally substituted by 1 to 3 halogens; (g) 5 to6-membered monocyclic aromatic heterocyclic group; (h) phenoxy; (i)halogen; or (j) hydroxy, and particularly, (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy and halogen; (c) C₃-C₇ cycloalkyl which maybe optionally substituted by 1 to 7 groups selected from C₁-C₆ alkyl,C₁-C₆ halogenoalkyl and halogen; (d) C₁-C₆ alkoxy which may beoptionally substituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; or (e) halogen ispreferable.

R⁵ and R⁶ are each independently and preferably hydrogen or alkyl,particularly hydrogen.

n is preferably 0 or 1.

The number of the substituent in the “optionally substitutedaminocarbonyl” of X may be one. As for such substituent, alkyl, alkoxyand nitrile can be mentioned for example.

The number of the substituents in the “optionally substituted alkanoyl”of X may be one or more (for example, 1 to 3), and the substituents maybe the same or different. As for such substituents, halogen can bementioned for example.

X is preferably (a) carboxy; (b) C₁-C₆ alkoxycarbonyl; (c) hydroxy-C₁-C₆alkyl; (d) aminocarbonyl wherein a nitrogen atom may be optionallysubstituted by one group selected from C₁-C₆ alkyl, C₁-C₆ alkoxy andnitrile; (e) C₂-C₇ alkanoyl which may be optionally substituted by 1 to3 halogens. Particularly (a) carboxy or (b) aminocarbonyl wherein anitrogen atom may be optionally substituted by one group selected fromC₁-C₆ alkyl, C₁-C₆ alkoxy and nitrile is preferable, and specificallycarboxy is preferable.

The pharmaceutically acceptable salt of a compound of formula (I)includes an alkali metal salt of lithium, sodium, potassium, etc.; agroup-II metal salt of calcium, magnesium, etc.; a salt with zinc oraluminum; a salt with amine such as ammonia, choline, diethanolamine,lysine, ethylenediamine, t-butylamine, t-octylamine,tris(hydroxymethyl)aminomethane, N-methyl-glucosamine, triethanolamine,dehydroabietylamine; a salt with inorganic acid such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid; a salt with organic acid such as formic acid, aceticacid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaricacid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid; or asalt with acidic amino acid such as aspartic acid, glutamic acid.

The pharmaceutically acceptable salt of a compound of formula (I)includes an intramolecular salt, a hydrate, and a solvate thereof.

The term “prodrug” refers to a compound which is converted in the bodyinto an activated form having pharmacological effects, for example byhydrolysis in the blood. Examples of the pharmaceutically acceptableprodrug are described in the literatures [T. Higuchi and V. Stella,Prodrugs as Novel Drug Delivery Systems, “Bioreversible Carriers in DrugDesign”, edited by Edward B. Roche, American Pharmaceutical Associationand Pergamon Press, A. C. S. Symposium Series, Vol. 14, (1987); and D.Fleisher, R. Bong and B. H. Stewart, “Improved oral drug delivery:Solubility limitations overcome by the use of prodrugs”, Advanced DrugDelivery Reviews (1996) 19(2): 115-130]. The prodrug wherein a compoundof formula (I) is carboxylic acid compound includes an ester such asmethyl ester, ethyl ester, a double ester.

The compound of the present invention may optionally have one or moreasymmetric carbon atoms which are contained in any one of substituentgroups. A compound of formula (I) may exist in the form of enantiomer ordiastereomer or a mixture thereof. The compound of the present inventionencompasses a mixture of stereoisomers, or pure or substantially pureisomers. A compound of formula (I) which is obtained in the form ofdiastereomer or enantiomer may be separated by a conventional methodknown in the art, for example chromatography or fractionalcrystallization.

In a preferable embodiment of the present invention, R¹ is (a) hydrogen;(b) C₁-C₆ alkyl which may be optionally substituted by 1 to 7 groupsselected from C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen, oxo and hydroxy;(c) C₃-C₇ cycloalkyl which may be optionally substituted by 1 to 7groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; (d) C₁-C₆alkoxy which may be optionally substituted by 1 to 7 groups selectedfrom C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen and hydroxy; (e) phenylwhich may be optionally substituted by 1 to 3 groups selected from C₁-C₆alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl,C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (f) halogen; or (g)nitrile,

R^(2a), R^(2b), R^(2c) and R^(2d) are each independently (a) hydrogen;(b) C₁-C₆ alkyl which may be optionally substituted by 1 to 7 groupsselected from C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, halogen, oxo and hydroxy;(c) C₃-C₇ cycloalkyl which may be optionally substituted by 1 to 7groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; (d) C₁-C₆alkoxy which may be optionally substituted by 1 to 7 groups selectedfrom C₁-C₆ alkoxy, C₃-C₇ cycloalkyl and halogen; (e) phenyl which may beoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy,C₁-C₆ halogenoalkoxy and halogen; (f) 5 to 6-membered monocyclicaromatic heterocyclic group which may be optionally substituted by 1 to3 groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxyand halogen; (g) 4 to 7-membered monocyclic non-aromatic heterocyclicgroup which may be optionally substituted by 1 to 3 groups selected fromC₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (h)halogen; or (i) nitrile,

R^(3a), R^(3b), R^(3c) and R^(3d) are each independently (a) hydrogen;(b) C₁-C₆ alkyl which may be optionally substituted by 1 to 7 groupsselected from C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl (in which thecycloalkyl and halogenocycloalkyl may be each independently andoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl andC₁-C₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, phenyl, 5 to6-membered monocyclic aromatic heterocyclic group, 4 to 7-memberedmonocyclic non-aromatic heterocyclic group (in which the phenyl,aromatic heterocyclic group and non-aromatic heterocyclic group may beeach independently and optionally substituted by 1 to 3 groups selectedfrom C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy and halogen),halogen, oxo and hydroxy; (c) C₃-C₇ cycloalkyl which may be optionallysubstituted by 1 to 7 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, halogen and hydroxy;(d) C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 groupsselected from C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl (in which thecycloalkyl and halogenocycloalkyl may be each independently andoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl andC₁-C₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, phenyl, 5 to6-membered monocyclic aromatic heterocyclic group, 4 to 7-memberedmonocyclic non-aromatic heterocyclic group (in which the phenyl,aromatic heterocyclic group and non-aromatic heterocyclic group may beeach independently and optionally substituted by 1 to 3 groups selectedfrom C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen),halogen and hydroxy; (e) C₃-C₇ cycloalkoxy which may be optionallysubstituted by 1 to 7 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, halogen and hydroxy;(f) phenyl which may be optionally substituted by 1 to 3 groups selectedfrom C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (g)5 to 6-membered monocyclic aromatic heterocyclic group which may beoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy,C₁-C₆ halogenoalkoxy and halogen; (h) 4 to 7-membered monocyclicnon-aromatic heterocyclic group which may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxyand halogen; (i) phenoxy which may be optionally substituted by 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl,C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy andhalogen; (j) halogen; or (k) hydroxy, or

two substituent groups selected from R^(3a), R^(3b), R^(3c) and R^(3d)combine each other to form oxo,

R⁵ and R⁶ are each independently (a) hydrogen; (b) C₁-C₆ alkyl; (c)C₁-C₆ halogenoalkyl; (d) C₃-C₇ cycloalkyl; or (e) C₃-C₇halogenocycloalkyl, or R⁵ and R⁶ combine each other at their terminalstogether with the adjacent carbon atom to form 3 to 7-membered alicyclicmonocyclic hydrocarbon,

X is (a) carboxy; (b) C₁-C₆ alkoxycarbonyl; (c) hydroxy-C₁-C₆ alkyl; (d)aminocarbonyl wherein a nitrogen atom may be optionally substituted byone group selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and nitrile; or (e)C₂-C₇ alkanoyl which may be optionally substituted by 1 to 3 halogens.

In another preferable embodiment of the present invention, Ring A isquinoline, isoquinoline or pyrrolopyridine.

In another further preferable embodiment of the present invention, thecompound of the present invention is represented by the followingformula (I-A):

wherein a group of formula:

is bicyclic aromatic heterocycle comprised of pyridine fused with (a)benzene or (b) monocyclic aromatic heterocycle (wherein one of Y and Zis CR^(2d), and the other is a chemical bond), and other symbols are thesame as defined above. In this embodiment, a group of formula:

is preferably a group of formula:

wherein the symbols are the same as defined above.

In another preferable embodiment of the present invention, Ring C isbenzene, and X is carboxy and binds to Ring C at 4-position to theaminosulfonyl moiety.

In another preferable embodiment of the present invention, the compoundof the present invention is represented by the following formula (I-B):

wherein symbols are the same as defined above.

In another preferable embodiment of the present invention, Ring A, R¹,R^(2a), R^(2b), R^(2c) and R^(2d) are represented by the followingformula:

wherein symbols are the same as defined above.

In another preferable embodiment of the present invention, Ring B is (a)monocyclic or bicyclic aromatic hydrocarbon; or (b) monocyclic orbicyclic aromatic heterocycle, and n is 0 or 1. More preferably, Ring Bis benzene, naphthalene, tetrahydronaphthalene, indane, pyridine,indole, dihydrobenzofuran, dihydroisobenzofuran, or benzothiophene,particularly benzene, naphthalene (particularly, naphthalen-2-yl),tetrahydronaphthalene (particularly, 1,2,3,4-tetrahydronaphthalen-6-yl),indane (particularly, indan-1-yl or indan-5-yl), pyridine (particularly,pyridin-2-yl) or benzothiophene (particularly, benzothiophen-2-yl).

In this embodiment, a preferable partial structure of formula:

is a group of formula (A):

wherein symbols are the same as defined above.

In another preferable embodiment, a partial structure of formula:

is a group of formula (B):

wherein symbols are the same as defined above.

In another preferable embodiment of the present invention, R¹ is (a)C₁-C₆ alkyl which may be optionally substituted by 1 to 7 halogens; (b)C₃-C₇ cycloalkyl; (c) C₁-C₆ alkoxy or (d) halogen,

R^(2a), R^(2b) and R^(2c) are hydrogen,

R^(2d) is (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 halogens; (c) C₃-C₇ cycloalkyl; or (d) C₁-C₆alkoxy,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl whichmay be optionally substituted by 1 to 7 groups selected from C₁-C₆alkyl, C₁-C₆ halogenoalkyl, and halogen; (d) C₁-C₆ alkoxy which may beoptionally substituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, and halogen; or (e) halogen,

R^(3c) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In another preferable embodiment of the present invention, a partialstructure of formula:

is a group of formula (C):

wherein p is 1 or 2, and other symbols are the same as defined above,

R¹ is (a) C₁-C₆ alkyl which may be optionally substituted by 1 to 7halogens; (b) C₃-C₇ cycloalkyl; (c) C₁-C₆ alkoxy; or (d) halogen,

R^(2a) and R^(2b) are hydrogen,

R^(2d) is (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 halogens; (c) C₃-C₇ cycloalkyl; or (d) C₁-C₆alkoxy,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl whichmay be optionally substituted by 1 to 7 groups selected from C₁-C₆alkyl, C₁-C₆ halogenoalkyl, and halogen; (d) C₁-C₆ alkoxy which may beoptionally substituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, and halogen; or (e) halogen.

In another preferable embodiment of the present invention, a partialstructure of formula (A):

is the following partial structure of formula (A-I):

wherein the symbols are the same as defined above,

Ring B is benzene or pyridine (particularly, pyridin-2-yl),

R¹ is methyl, trifluoromethyl, isopropyl, cyclopropyl, or methoxy,

R^(2d) is (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 halogens; (c) C₃-C₇ cycloalkyl; or (d) C₁-C₆alkoxy,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens; or(e) halogen,

R^(3c) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In this embodiment, a preferable partial structure of formula (A):

is the following partial structure of formula (A-II):

Ring B is benzene or pyridine (particularly, pyridin-2-yl),

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens; or(e) halogen,

R^(3c) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In this embodiment, more preferably, R^(3a) and R^(3b) are eachindependently (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl and halogen;(c) C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens;or (e) halogen.

In another preferable embodiment of the present invention, a preferablepartial structure of formula (A):

is the following partial structure of formula (A-III):

Ring B is benzene,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens; or(e) halogen,

R^(3c) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In this embodiment, more preferably, R^(3a) and R^(3b) are eachindependently (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl and halogen;(c) C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens;or (e) halogen.

In another preferable embodiment of the present invention, a preferablepartial structure of formula (A):

is the following partial structure of formula (A-IV):

wherein Me is methyl, and the other symbol is the same as defined above,

Ring B is benzene,

R^(2d) is (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 halogens; or (c) C₃-C₇ cycloalkyl,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens; or(e) halogen,

R^(3c) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In this embodiment, more preferably, R^(2d) is hydrogen, isopropyl orcyclopropyl,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl and halogen; (c) C₁-C₆ alkoxy which may be optionallysubstituted by 1 to 7 halogens; or (e) halogen.

In another preferable embodiment of the present invention, a preferablepartial structure of formula (A):

is the following partial structure of formula (A-V):

wherein the symbol is the same as defined above,

Ring B is benzene,

R¹ is isopropyl or methoxy,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl (in which the cycloalkyl may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C₁-C₆alkoxy, C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens; or(e) halogen,

R^(3a) and R^(3d) are hydrogen,

R⁵ and R⁶ are hydrogen,

n is 1.

In this embodiment, more preferably, R^(3a) and R^(3b) are eachindependently (a) hydrogen; (b) C₁-C₆ alkyl which may be optionallysubstituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl and halogen;(c) C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 halogens;or (e) halogen.

In another preferable embodiment of the present invention, a preferablepartial structure of formula:

is a group of formula (D):

wherein the symbols are the same as defined above,

R^(3a) and R^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkylwhich may be optionally substituted by 1 to 7 groups selected from C₃-C₇cycloalkyl and halogen; (c) C₁-C₆ alkoxy which may be optionallysubstituted by 1 to 7 halogens; or (e) halogen.

A preferable compound of the present invention is selected from thegroup consisting of:

-   4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic    acid;-   4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid;-   4-({1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic    acid;-   4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-({(3-methylquinolin-2-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic    acid;-   4-{[[4-fluoro-3-(trifluoromethyl)benzyl]    (3-methylquinolin-2-yl)amino]sulfonyl}benzoic acid;-   4-{[(4-t-butylbenzyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid;-   4-{[[4-(cyclopropylmethyl)benzyl](4-methylisoquinolin-3-yl)-amino]sulfonyl}benzoic    acid;-   4-{[[4-fluoro-3-(trifluoromethyl)benzyl]    (4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic acid;-   4-{[(4-methylisoquinolin-3-yl)(2-naphthylmethyl)amino]sulfonyl}benzoic    acid;-   4-({(1-methoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic    acid;-   4-({(4-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic    acid;-   4-{[(4-methylisoquinolin-3-yl)(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)amino]sulfonyl}-benzoic    acid;-   4-{[(2,3-dihydro-1H-inden-5-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid;-   4-{[[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-{[[(2,2-dimethyl-2,3-dihydro-1H-inden-5-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-{[[(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-{[[(1-benzothiophen-2-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid;-   4-({(1,4-dimethylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic    acid; and-   4-({(4-methylisoquinolin-3-yl)[4-(2,2,2-trifluoro-1-methoxy-1-methylethyl)benzyl]amino}-sulfonyl)benzoic    acid; or    a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another preferable compound of the present invention is selected fromthe group consisting of:

-   4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic    acid;-   4-({(1-methoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic    acid;-   4-({(1-isopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic    acid;-   4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-({(4-cyclopropylisoquinolin-3-yl)    [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid;-   4-{[{3-chloro-4-[cyclopropyl    (difluoro)methyl]benzyl}(1-cyclopropyl-4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid;-   4-{[{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoic    acid;-   4-[((4-cyclopropylisoquinolin-3-yl){[5-(trifluoromethyl)pyridin-2-yl]methyl}amino)    sulfonyl]-benzoic acid;-   4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(4-cyclopropylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-{[{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-cyclopropylisoquinolin-3-yl)amino]-sulfonyl}benzoic    acid;-   4-({(4-cyclopropylisoquinolin-3-yl)[5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]amino}-sulfonyl)benzoic    acid;-   4-({{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}[4-(trifluoromethyl)isoquinolin-3-yl]-amino}sulfonyl)benzoic    acid; and-   4-({{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}[4-(trifluoromethyl)isoquinolin-3-yl]-amino}sulfonyl)benzoic    acid; or    a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The compound of the present invention has a novel structure whereinbicyclic aromatic heterocycle in which pyridine is condensed withbenzene or pyridine is condensed with monocyclic aromatic heterocyclebinds to a sulfonylamino moiety, and shows excellent TRPM8 antagonisticactivity in the menthol-induced calcium influx inhibiting test. Thecompound of the present invention also shows excellent inhibitoryeffects on Wet Dog Shakes induced by TRPM8 agonist (e.g., menthol oricilin) in rat, for example.

Accordingly, the compound of the present invention is useful for theprevention and treatment of

-   (a) chronic pain: such as neuropathic pain (for example cold    allodynia, diabetic neuropathy, postherpetic neuralgia, complex    regional pain syndrome, chemotherapy-induced peripheral neuropathy,    trigeminal neuralgia, post stroke pain, spinal cord injury pain,    neuralgia, or nerve injury-induced neuropathic pain), nociceptive    pain (for example rheumatoid arthritis, osteoarthritis,    postoperative pain, or myofascial pain), or mixed pain (for example    cancer pain, fibromyalgia syndrome, or chronic low back pain);-   (b) cephalalgia: such as migraine, or cluster or tension headache;-   (c) urologic disease: such as detrusor overactivity, overactive    bladder, urinary incontinence, neurogenic bladder, detrusor    hyperreflexia, idiopathic detrusor overactivity, detrusor    instability, interstitial cystitis, benign prostatic hyperplasia,    chronic prostatitis, or lower urinary tract symptom;-   (d) carcinoma: such as prostate cancer, or breast cancer;-   (e) respiratory disease: such as asthma, COPD (chronic obstructive    pulmonary disease), or pulmonary hypertension;-   (f) gastrointestinal disease: such as irritable bowel syndrome;-   (g) psychiatric disease: such as mood disorder (for example    depression, or bipolar disorder), or anxiety disorder (for example    anxiety);-   (h) neurological disease: such as neurodegenerative disease, or    stroke; or-   (i) dermatosis: such as pruritus.    The compound of the present invention is preferably useful for the    prevention and treatment of chronic pain or urologic disease,    particularly chronic pain.

The compound of the present invention or a pharmaceutically acceptablesalt thereof, or a prodrug thereof may be administered orally orparenterally, and may be used in the form of suitable pharmaceuticalformulation. The pharmaceutical formulation suitable for oraladministration includes a solid formulation such as tablet, granule,capsule, powder, or a liquid formulation, suspension, emulsion. Thepharmaceutical formulation suitable for parenteral administrationincludes suppository; injection or intravenous infusion in which waterfor injection, physiological saline or aqueous glucose solution is used;and an inhalant formulation.

The pharmaceutical composition herein may comprise about 0.01 mg/kg toabout 100 mg/kg (preferably, about 0.01 mg/kg to about 50 mg/kg, morepreferably about 0.01 mg/kg to about 30 mg/kg) of the active ingredientper a unit dose, for example per a tablet, capsule, powder, injection,suppository, teaspoon, and may be administered in the dose of about 0.01mg/kg/day to about 100 mg/kg/day (preferably, about 0.01 mg/kg/day toabout 50 mg/kg/day, more preferably about 0.01 mg/kg/day to about 30mg/kg/day). The pharmaceutical composition comprising any one ofcompounds defined herein and pharmaceutically acceptable carriers may beused in the method of treating diseases described herein. The dosageform may comprise about 0.01 mg/kg to about 100 mg/kg (preferably, about0.01 mg/kg to about 50 mg/kg, more preferably about 0.01 mg/kg to about30 mg/kg) of the active ingredient, and may be formed in any formssuitable for the selected administration mode. The dose may varyaccording to the administration routes, the needs of subjects, theseverities of conditions to be treated and compounds to be used. Thepharmaceutical composition may be daily or periodically administered.

Compound (I) of the present invention may be prepared by the methods ofthe following scheme 1, 2 or 3, but preparation methods of Compound (I)are not limited thereto.

It is required and/or desired that sensitive or reactive groups in theinterest molecule may be protected during any preparation processes ofthe compound of the present invention. The protection may be achieved byconventional protective groups. The protective groups and common usesthereof are described in T. W. Greene, et al., “Protecting Groups inOrganic Synthesis”, John Wiley & Sons, New York, 2006. The protectivegroup may be removed in the subsequent process by a conventional method.

(In the above scheme, LG is a leaving group and includes halogen such aschlorine, bromine, substituted sulfonyloxy such as p-toluenesulfonyloxy,methanesulfonyloxy and trifluoromethylsulfonyloxy, and other symbols arethe same as defined above.)

Compound (IV) may be reacted with Compound (V) to give Compound (II).The resulting compound may be reacted with Compound (III) to giveCompound (I).

Step 1:

Compound (II) may be prepared by condensing Compound (IV) with Compound(V) in a solvent in the presence of a base.

Any solvents which do not affect the reaction may be preferably used asthe solvent in the condensation, and examples of the solvent includeether such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane;hydrocarbon such as toluene, hexane, xylene; halogenohydrocarbon such asdichloromethane, chloroform 1,2-dichloroethane; ester such as ethylacetate, butyl acetate; ketone such as acetone, butanone; amide such asN,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone; sulfoxide suchas dimethyl sulfoxide, and the following amines may be also used as thesolvent. These solvents may be used alone or in combination. Apreferable solvent in the reaction is amine such as pyridine; orhalogenohydrocarbon such as chloroform.

Any conventional bases may be used as the base, and examples of the baseinclude alkali metal amide such as lithium diisopropylamide, sodiumamide, lithium bistrimethylsilylamide; alkali metal carbonate such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate; alkali metal phosphate such as sodiumphosphate, potassium phosphate; amine such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, preferably aminesuch as pyridine.

The reaction may be carried out at low temperature, room temperature orhigh temperature, for example at 0° C. to 120° C.

When two equimolar amount of compound of formula (V) are condensed withone equimolar amount of compound of formula (IV) in the condensationreaction and a sulfonimide compound is obtained, the sulfonimidecompound may be treated with tetrabutylammonium fluoride to give thecorresponding Compound (II).

Step 2:

Compound (I) may be prepared by condensing Compound (II) with Compound(III) in a solvent in the presence of a base.

Any solvents which do not affect the reaction may be preferably used asthe solvent in the condensation, and examples of the solvent includeether such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane;hydrocarbon such as toluene, hexane, xylene; ester such as ethylacetate, butyl acetate; ketone such as acetone, butanone; amide such asN,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone; sulfoxide suchas dimethyl sulfoxide, and the following amines may be also used as thesolvent. These solvents may be used alone or in combination. Apreferable solvent in the reaction is amide such asN,N-dimethylformamide.

Any conventional bases may be used as the base, and examples of the baseinclude alkali metal amide such as lithium diisopropylamide, sodiumamide, lithium bistrimethylsilylamide; alkali metal carbonate such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate; alkali metal phosphate such assodium phosphate, potassium phosphate; amine such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, preferably alkalimetal carbonate such as potassium carbonate.

The reaction may be carried out at low temperature, room temperature orhigh temperature, for example at −20° C. to 80° C.

(In the above scheme, symbols are the same as defined above.)

Compound (IV) may be reacted with Compound (V) to give Compound (II).The resulting compound may be reacted with Compound (VI) to giveCompound (I).

Step 1:

Compound (II) may be prepared according to the method of Scheme 1, Step1.

Step 2:

Compound (I) may be prepared by Mitsunobu reaction of Compound (II) withCompound (VI) in a solvent.

Mitsunobu reaction may be carried out in an appropriate solvent in thepresence of phosphine and azodicarboxylate compound.

Examples of phosphine include triphenylphosphine, diphenyl(2-pyridyl)phosphine, (4-dimethylaminophenyl)diphenylphosphine,isopropyldiphenylphosphine, diethyl-phenylphosphine,dicyclohexylphenylphosphine, tributylphosphine, tri-t-butylphosphine,tricyclohexylphosphine. Examples of the azodicarboxylate compoundinclude diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibutylazodicarboxylate, azodicarbonyl dipiperazine, tetramethylazodicarboxamide. The reaction may be carried out in the presence ofcyanomethylenetributylphosphorane in place of phosphine andazodicarboxylate compound.

Any solvents which do not affect the reaction may be preferably used asthe solvent, and examples of the solvent include ether such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon such astoluene, hexane, xylene; ester such as ethyl acetate, butyl acetate;ketone such as acetone, butanone; amide such as N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone andN-methylpyrrolidone; sulfoxide such as dimethyl sulfoxide. Thesesolvents may be used alone or in combination. A preferable solvent inthe reaction is ether such as tetrahydrofuran.

The reaction may be carried out at low temperature, room temperature orhigh temperature, for example at −20° C. to 80° C.

(In the above scheme, symbols are the same as defined above.)

Compound (VIII) may be reacted with Compound (IX) to give Compound(VII). The resulting compound may be reacted with Compound (V) to giveCompound (I).

Step 1:

Compound (VII) may be prepared by condensing Compound (VIII) withCompound (IX) in a solvent or without a solvent in the presence of abase.

Any solvents which do not affect the reaction may be preferably used asthe solvent in the condensation, and examples of the solvent includeether such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane;hydrocarbon such as toluene, hexane, xylene; ester such as ethylacetate, butyl acetate; ketone such as acetone, butanone; amide such asN,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone; sulfoxide suchas dimethyl sulfoxide. These solvents may be used alone or incombination. The absence of solvent is preferable in the reaction.

A conventional bases may be used as the base, and examples of the baseinclude alkali metal amide such as lithium diisopropylamide, sodiumamide, lithium bistrimethylsilylamide; alkali metal carbonate such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate; alkali metal phosphate such as sodiumphosphate, potassium phosphate; amine such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine. Excess amounts ofCompound (IX) may be also used as the base. A preferable base in thereaction is excess amounts of Compound (IX).

The reaction may be carried out at high temperature, for example at 100°C. to 250° C., and may be preferably carried out by microwaveirradiation.

Step 2:

Compound (I) may be prepared according to the method of Scheme 1, Step1.

Further, an interconversion may be carried out by a conventional methodfor Compound (I) prepared in the above preparation, or for anintermediate compound obtained during the preparation of Compound (I).

Compound (I) wherein Ring B is indole and an intermediate compoundthereof may be prepared by oxidizing Compound (I) wherein Ring B isindoline and an intermediate compound thereof, respectively. Theoxidation reaction may be carried out in an appropriate solvent in thepresence of an oxidizing agent.

The oxidizing agent includes 2,3-dichloro-5,6-dicyano-p-benzoquinone.The solvent may be selected from any solvents which do not affect thereaction, and examples of the solvent include aromatic hydrocarbon suchas toluene and xylene; ether such as tetrahydrofuran,1,2-dimethoxyethane and 1,4-dioxane; halogenohydrocarbon such asdichloromethane, chloroform and 1,2-dichloroethane. These solvents maybe used alone or in combination.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedphenyl, and an intermediate compound thereof (hereinafter may also bereferred to as the compound containing optionally substituted phenyl)may be prepared by coupling Compound (I) wherein the substituent groupR¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) ishalogen (particularly, bromine, iodine), and an intermediate compoundthereof (hereinafter may also be referred to as the compound containinghalogen), respectively, with Ar¹B(OH)₂ or cyclic borate ester thereof,Ar¹BF₃K or Ar¹Sn(n-Bu)₃ (wherein Ar¹ is optionally substituted phenyl,and n-Bu is butyl), etc.

The coupling reaction may be carried out by a conventional aryl couplingreaction, for example Suzuki coupling (cf., Suzuki et al., Synth.Commun. 11:513 (1981); Suzuki, Pure and Appl. Chem. 57:1749-1758 (1985);Suzuki et al., Chem. Rev. 95:2457-2483 (1995); Shieh et al., J. Org.Chem. 57:379-381 (1992); Martin et al., Acta Chemica Scand inavica47:221-230 (1993); Wallace et al., Tetrahedron Lett. 43:6987-6990 (2002)and Molander et al., J. Org. Chem. 68:4302-4314 (2003)) and Stillecoupling (cf., Stille, Angew. Chem. Int. Ed. Engl. 25:508-524 (1986) andLiebeskind et al., J. Org. Chem. 59:5905-5911 (1994)).

The coupling reaction may be carried out in an appropriate solvent withor without a ligand, base and additive in the presence of Pd catalyst.

Examples of the Pd catalyst includetetrakis(triphenylphosphine)palladium (0), palladium (II) acetate,bis(acetonitrile)dichloropalladium (II),dichlorobis(triphenylphosphine)palladium (II), a complex of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) withdichloromethane, tris(dibenzylidene-acetone)dipalladium (0)-chloroformadduct and palladium (II) chloride. Examples of the base include alkalimetal carbonate such as cesium carbonate, potassium carbonate, sodiumcarbonate and sodium hydrogen carbonate; alkali metal phosphate such astribasic potassium phosphate, sodium phosphate and sodium hydrogenphosphate; amine such as N,N-diisopropylethylamine; alkali metalfluoride such as cesium fluoride and potassium fluoride; alkali metalalkoxide such as sodium-t-butoxide, potassium-t-butoxide. Examples ofthe ligand include triphenylphosphine, tributylphosphine,tri-t-butylphosphonium tetrafluoroborate,1,3-bis(diphenylphosphino)propane,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,1′-bis(diphenylphosphino)ferrocene,2-(di-tert-butylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-(dicyclohexylphosphino)biphenyl, di(1-adamantyl)butylphosphine.Examples of the additive include copper (I) iodide.

The solvent may be selected from any solvents which do not affect thecoupling reaction, and examples of the solvent include aromatichydrocarbon such as toluene and xylene; ether such as tetrahydrofuran,1,2-dimethoxyethane and 1,4-dioxane; amide such asN,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone; alcohol such asmethanol, ethanol and 2-propanol; water. These solvents may be usedalone or in combination.

The coupling reaction may be carried out at room temperature or hightemperature, for example at 20° C. to 150° C.

Compound (I) wherein the substituent group R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedmonocyclic aromatic heterocyclic group or optionally substitutedmonocyclic non-aromatic heterocyclic group and an intermediate compoundthereof may be prepared by coupling Compound (I) wherein the substituentgroup R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d)is halogen (particularly, bromine, iodine) and an intermediate compoundthereof, respectively, with Ar²B(OH)₂, Ar²BF₃K or Ar²Sn(n-Bu)₃ (whereinAr² is optionally substituted monocyclic aromatic heterocyclic group oroptionally substituted monocyclic non-aromatic heterocyclic group, andn-Bu is the same as defined above).

This reaction may be carried out according to the method of the couplingreaction as in the above preparation of the compound containingoptionally substituted phenyl from the compound containing halogen.

Compound (I) wherein the substituent group R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedmonocyclic non-aromatic heterocyclic group comprising a nitrogen atom asa ring atom and binds to Ring A or Ring B via the nitrogen atom and anintermediate compound thereof may be prepared by coupling Compound (I)wherein the substituent group R^(2a), R^(2b), R^(2c), R^(2d), R^(3a),R^(3b), R^(3c) or R^(3d) is halogen (particularly, bromine, iodine) andan intermediate compound thereof, respectively, with the correspondingmonocyclic non-aromatic heterocyclic group wherein a nitrogen atom issubstituted by hydrogen.

This reaction may be carried out by a conventional amination method, forexample Buchwald-Hartwig amination method (cf., Yang, B. H.; Buchwald,S. L. J. Organomet. Chem. 576 (1999) 125-146).

Specifically, it may be carried out according to the method of thecoupling reaction as in the above preparation of the compound containingoptionally substituted phenyl from the compound containing halogen.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substituted alkyland an intermediate compound thereof may be prepared by alkylatingCompound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen (particularly,bromine, iodine) and an intermediate compound thereof, respectively.

The alkylation reaction may be carried out by treating Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is halogen or an intermediate compoundthereof with alkyllithium (e.g., butyllithium), followed by thecorresponding halogenoalkyl (e.g., iodoalkyl) in an appropriate solvent(e.g., ether such as tetrahydrofuran).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is methyl and an intermediatecompound thereof may be prepared by coupling Compound (I) wherein thesubstituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b),R^(3c) or R^(3d) is halogen (particularly, bromine, iodine) and anintermediate compound thereof, respectively, with methyl borate orcyclic borate ester thereof, trimethylboroxine or potassiummethyltrifluoroborate.

This reaction may be carried out according to the method of the couplingreaction as in the above preparation of the compound containingoptionally substituted phenyl from the compound containing halogen.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substituted C₂-C₆alkyl and an intermediate compound thereof may be prepared by couplingCompound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen (particularly,bromine, iodine) and an intermediate compound thereof, respectively,with R⁷B(OH)₂ or R⁷BF₃K (wherein R⁷ is optionally substituted C₂-C₆alkenyl) to give an optionally substituted alkenyl compound, followed byhydrogenation.

The preparation reaction of the optionally substituted alkenyl compoundmay be carried out according to the method of the coupling reaction asin the above preparation of the compound containing optionallysubstituted phenyl from the compound containing halogen.

The hydrogenation reaction of the optionally substituted alkenylcompound may be carried out under hydrogen atmosphere in an appropriatesolvent in the presence of a catalyst.

Examples of the catalyst include palladium carbon, palladium hydroxide,and platinum oxide.

The solvent may be selected from any solvents which do not affect thereaction, and examples of the solvent include ether such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; alcohol such asmethanol, ethanol and 2-propanol; ester such as ethyl acetate;carboxylic acid such as acetic acid. These solvents may be used alone orin combination.

The reaction may be carried out at room temperature or high temperature,for example at 20° C. to 80° C.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is cyclopropylmethyl and anintermediate compound thereof may be prepared by coupling Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is halogen (particularly, bromine,iodine) and an intermediate compound thereof, respectively, with allyltributyl tin, followed by cyclopropylation of double bonds of theresulted allyl.

The preparation reaction of the allyl compound may be carried outaccording to the method of the coupling reaction as in the abovepreparation of the compound containing optionally substituted phenylfrom the compound containing halogen.

The cyclopropylation reaction may be carried out in an appropriatesolvent in the presence of dihalogenomethane and diethylzinc.

Examples of the dihalogenomethane include chloroiodomethane anddiiodomethane.

The solvent may be selected from any solvents which do not affect thecyclopropylation reaction, and examples of the solvent includehalogenohydrocarbon such as dichloromethane, chloroform and1,2-dichloroethane. These solvents may be used alone or in combination.

The reaction may be carried out at room temperature or high temperature,for example at 20° C. to 80° C.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is oxo-substituted alkyl and anintermediate compound thereof may be prepared byN-methoxy-N-methylamidation of Compound (I) wherein the substituentgroup R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) orR^(3d) is alkyl which is substituted by hydroxy and oxo on the samecarbon atom and an intermediate compound thereof, respectively, followedby alkylation or cycloalkylation of the resulting amide with R⁸Li orR⁸MgLG¹ (wherein R⁸ is the corresponding optionally substituted alkyl orthe corresponding optionally substituted cycloalkyl, and LG¹ ishalogen).

The N-methoxy-N-methylamidation reaction may be carried out in anappropriate solvent (e.g., halogenohydrocarbon such as dichloromethane,chloroform or dichloroethane) with or without N-hydroxybenzotriazole inthe presence of amine (e.g., N,O-dimethylhydroxyamine orN,O-dimethylhydroxyamine hydrochloride), a condensing agent (e.g.,carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride) and base (e.g., amine such as triethylamine).

The alkylation or cycloalkylation reaction may be carried out in anappropriate solvent (e.g., ether such as tetrahydrofuran or hydrocarbonsuch as hexane, or a mixture thereof).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedalkanoyl and an intermediate compound thereof may be prepared bycoupling Compound (I) wherein the substituent group R¹, R^(2a), R^(2b),R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen(particularly, bromine, iodine) and an intermediate compound thereof,respectively, with R⁹Sn(n-Bu)₃ (wherein R⁹ is 1-alkoxy-1-alken-1-yl, andn-Bu is butyl) to give an alkenyl ether compound, followed byhydrolysis. The preparation reaction of the alkenylether compound may becarried out according to the method of the coupling reaction as in theabove preparation of the compound containing optionally substitutedphenyl from the compound containing halogen.

The hydrolysis may be carried out in an appropriate solvent (e.g., ethersuch as tetrahydrofuran; ester such as ethyl acetate; or water, or amixture thereof) in the presence of acid (e.g., inorganic acid such ashydrogen chloride).

Alternatively, Compound (I) wherein the substituent group R¹, R^(2a),R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionallysubstituted alkanoyl and an intermediate compound thereof may beprepared by alkanoylation of Compound (I) wherein the substituent groupR¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) ishalogen (particularly, bromine, iodine) and an intermediate compoundthereof, respectively.

The alkanoylation reaction may be carried out by treating Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is halogen or an intermediate compoundthereof with alkyllithium (e.g., butyllithium), followed by thefollowing compound of formula:

wherein R¹⁰ is optionally substituted alkyl and Me is methyl,in an appropriate solvent (e.g., ether such as tetrahydrofuran orhydrocarbon such as hexane, or a mixture thereof).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedcycloalkyl and an intermediate compound thereof may be prepared bycoupling Compound (I) wherein the substituent group R¹, R^(2a), R^(2b),R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen(particularly, bromine, iodine) and an intermediate compound thereof,respectively, with R¹¹B(OH)₂ or R¹¹BF₃K (wherein R¹¹ is optionallysubstituted cycloalkyl).

This reaction may be carried out according to the method of the couplingreaction as in the above preparation of the compound containingoptionally substituted phenyl from the compound containing halogen.

Alternatively, Compound (I) wherein the substituent group R¹, R^(2a),R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionallysubstituted cycloalkyl and an intermediate compound thereof may beprepared by coupling Compound (I) wherein the substituent group R¹,R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) ishalogen (particularly, bromine, iodine) and an intermediate compoundthereof, respectively, with R¹²B(OH)₂ or R¹²BF₃K (wherein R¹² isoptionally substituted cycloalkenyl) to give a optionally substitutedcycloalkenyl compound, followed by hydrogenation.

The preparation reaction of the optionally substituted cycloalkenylcompound may be carried out according to the method of the couplingreaction as in the above preparation of the compound containingoptionally substituted phenyl from the compound containing halogen.

The hydrogenation of the cycloalkenyl compound may be carried outaccording to the method of the above hydrogenation of the optionallysubstituted C₂-C₆ alkenyl compound.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is hydrogen and an intermediatecompound thereof may be prepared by reducing Compound (I) wherein thesubstituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b),R^(3c) or R^(3d) is halogen (particularly, bromine, iodine) and anintermediate compound thereof, respectively.

The reduction reaction may be carried out under hydrogen atmosphere inan appropriate solvent with or without a base in the presence of acatalyst.

Examples of the catalyst include palladium carbon, palladium hydroxideand platinum oxide. Examples of the base include amine such astriethylamine.

The solvent may be selected from any solvents which do not affect thereaction, and examples of the solvent include ether such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; alcohol such asmethanol, ethanol and 2-propanol; ester such as ethyl acetate;carboxylic acid such as acetic acid. These solvents may be used alone orin combination.

The reaction may be carried out at room temperature or high temperature,for example at 20° C. to 80° C.

Alternatively, the reduction reaction may be carried out in anappropriate solvent (e.g., secondary alcohol such as 2-propanol) with orwithout a ligand (e.g., triphenylphosphine) in the presence of Pdcatalyst (e.g., palladium (II) acetate) and base (e.g., alkali metalcarbonate such as potassium carbonate).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is fluoroalkyl and anintermediate compound thereof may be prepared by coupling Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is halogen (particularly, iodine) andan intermediate compound thereof, respectively, with methylfluorosulfonyldifluoroacetate, potassium fluoroalkyl carboxylate orfluoroalkyl trimethylsilane.

The coupling reaction may be carried out in an appropriate solvent withor without an additive in the presence of Cu complex.

Examples of the Cu complex include copper (I) bromide, copper (I) iodideor copper (I) thiophene-2-carboxylate, preferably copper (I) bromide andcopper (I) iodide. The reaction may be also carried out by adding anadditive. Examples of the additive include potassium fluoride.

Any solvents which do not affect the reaction may be preferably used,and examples of the solvent include ether such as tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane; amide such as N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone andN-methylpyrrolidone; aprotic polar solvent such as dimethyl sulfoxide,hexamethylphosphoric triamide. These solvents may be used alone or incombination. A preferable solvent in the reaction is a mixture of amidesuch as N,N-dimethylformamide and aprotic polar solvent such ashexamethylphosphoric triamide.

The reaction may be carried out at room temperature or high temperature,for example at 20° C. to 120° C.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl which is difluorinatedon the same carbon atom and an intermediate compound thereof may beprepared by difluorinating Compound (I) wherein the substituent groupR¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) isoxo-substituted alkyl and an intermediate compound thereof,respectively.

The difluorinating reaction may be carried out in an appropriate solvent(e.g., halogenohydrocarbon such as dichloromethane, chloroform ordichloroethane) or without a solvent with or without a catalyst (e.g.,alcohol such as methanol or ethanol) in the presence of a fluorinatingagent (e.g., diethylaminosulfur trifluoride orbis(2-methoxyethyl)aminosulfur trifluoride).

The reaction may be preferably carried out at 0° C. to 100° C.,particularly at 20° C. to 80° C.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkoxy-substituted alkyl andan intermediate compound thereof may be prepared by alkylating Compound(I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is hydroxy-substituted alkyl and anintermediate compound thereof, respectively, with R¹³LG² (wherein R¹³ isalkyl, and LG² is a leaving group and includes halogen such as bromine,iodine; substituted sulfonyloxy such as p-toluenesulfonyloxy,methanesulfonyloxy, trifluoromethanesulfonyloxy, and alkoxysulfonyloxy).

The alkylating reaction may be carried out in an appropriate solvent inthe presence of a base.

Any solvents which do not affect the reaction may be preferably used asthe solvent in the alkylation reaction, and examples of the solventinclude ether such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane;hydrocarbon such as toluene, hexane, xylene; ester such as ethylacetate, butyl acetate; amide such as N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone andN-methylpyrrolidone. These solvents may be used alone or in combination,preferably amide such as N,N-dimethylformamide.

Examples of the base include alkali metal hydride such as sodiumhydride, potassium hydride; alkali metal hydroxide such as sodiumhydroxide, potassium hydroxide; alkaline-earth metal hydroxide such ascalcium hydroxide, barium hydroxide; alkali metal alkoxide such assodium methoxide, sodium ethoxide, potassium ethoxide, potassiumt-butoxide; alkali metal amide such as lithium diisopropylamide, sodiumamide, lithium bistrimethylsilylamide; alkali metal carbonate such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, preferably alkali metal hydride such assodium hydride.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl which is substitutedon the same carbon atom by (a) C₁-C₃ perfluoroalkyl (e.g.,trifluoromethyl, pentafluoroethyl or heptafluoropropyl) and (b) hydroxyand an intermediate compound thereof may be prepared byperfluoroalkylating Compound (I) wherein the substituent group R¹,R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) isoxo-substituted alkyl and an intermediate compound thereof,respectively, with R¹⁴SiMe₃ (wherein R¹⁴ is perfluoroalkyl, and Me ismethyl).

The perfluoroalkylating reaction may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran) in the presence of afluoride ion source (e.g., tetrabutylammonium fluoride).

Compound (I) wherein two substituent groups selected from thesubstituent groups R^(3a), R^(3b), R^(3c) and R^(3d) are (a) C₁-C₃perfluoroalkyl (e.g., trifluoromethyl, pentafluoroethyl orheptafluoropropyl) and (b) hydroxy which are on the same carbon atomconstituting Ring B and an intermediate compound thereof may be preparedby perfluoroalkylating Compound (I) wherein two substituent groupsselected from the corresponding substituent groups R^(3a), R^(3b),R^(3c) and R^(3d) combine each other to form oxo and an intermediatecompound thereof, respectively, with R¹⁵SiMe₃ (wherein R¹⁵ isperfluoroalkyl, and Me is methyl).

This reaction may be carried out according to the method of the aboveperfluoroalkylating reaction of oxo-substituted alkyl.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl which is substitutedon the same carbon atom by cycloalkyl and hydroxy and an intermediatecompound thereof may be prepared by cycloalkylating Compound (I) whereinthe substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a),R^(3b), R^(3c) or R^(3d) is oxo-substituted alkyl and an intermediatecompound thereof, respectively, with R¹⁶L¹ or R¹⁶MgLG′ (wherein R¹⁶ iscycloalkyl, and LG¹ is halogen).

The cycloalkylating reaction may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is hydroxy-substituted alkyland an intermediate compound thereof may be prepared by reducingCompound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is oxo-substituted alkyl and anintermediate compound thereof, respectively.

The reduction reaction may be carried out in an appropriate solvent(e.g., alcohol such as methanol, ethanol) in the presence of a reducingagent (e.g., lithium borohydride, sodium borohydride).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl and an intermediatecompound thereof may be prepared by silane-reduction of Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is hydroxy-substituted alkyl and anintermediate compound thereof, respectively.

The reduction reaction may be carried out in an appropriate solvent(e.g., halogenohydrocarbon such as chloroform) or without a solvent inthe presence of an acid (e.g., carboxylic acid such as trifluoroaceticacid) and a reducing agent (e.g., trialkylsilane such astriethylsilane).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substituted alkyland attaches at a nitrogen atom constituting Ring A or Ring B and anintermediate compound thereof may be prepared by alkylating Compound (I)wherein the substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d) is hydrogen and an intermediatecompound thereof, respectively, with R¹⁷LG² (wherein R¹⁷ is optionallysubstituted alkyl, and LG² is a leaving group and includes halogen suchas bromine, iodine; substituted sulfonyloxy such asp-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy,and alkoxysulfonyloxy).

The preparation reaction of this compound may be carried out accordingto the method of the above alkylating reaction of hydroxy-substitutedalkyl, and a preferable base is alkali metal carbonate such as potassiumcarbonate, or alkali metal hydride such as sodium hydride.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedcycloalkyl and attaches at a nitrogen atom constituting Ring A or Ring Band an intermediate compound thereof (hereinafter may also be referredto as the compound containing optionally substituted cycloalkyl) may beprepared by coupling Compound (I) wherein the substituent group R¹,R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) ishydrogen and an intermediate compound thereof (hereinafter may also bereferred tows the compound containing hydrogen on the nitrogen atom),respectively, with R¹⁸B(OH)₂ or R¹⁸BF₃K (wherein R¹⁸ is optionallysubstituted cycloalkyl).

The coupling reaction may be carried out in an appropriate solvent(e.g., halogenohydrocarbon such as 1,2-dichloroethane) with or without aligand (e.g., diamine such as 2,2′-bipyridyl) in the presence of Cucatalyst (e.g., copper (II) acetate) and a base (e.g., alkali metalcarbonate such as sodium carbonate).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is optionally substitutedalkoxy and an intermediate compound thereof may be prepared byalkoxylating Compound (I) wherein the substituent group R¹, R^(2a),R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen(particularly, bromine or iodine) and an intermediate compound thereof,respectively.

The alkoxylating reaction may be carried out in an appropriate solvent(e.g., ether such as tetrahydrofuran) in the presence of thecorresponding alcohol and base (e.g., alkali metal hydride such assodium hydride).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is iodine and an intermediatecompound thereof may be prepared by iodinating Compound (I) wherein thesubstituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b),R^(3c) or R^(3d) is bromine and an intermediate compound thereof,respectively.

The iodinating reaction may be carried out in an appropriate solventwith or without a ligand in the presence of an iodinating agent and acatalyst.

Examples of the iodinating agent include sodium iodide. Examples of thecatalyst include copper (I) iodide. Examples of the ligand includediamine such as N,N′-dimethylethylenediamine, andN,N′-1,2-cyclohexanediamine.

The solvent may be selected from any solvents which do not affect thereaction, and examples of the solvent include ether such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alkylnitrile such asacetonitrile, propionitrile. These solvents may be used alone or incombination.

The reaction may be carried out at room temperature or high temperature,for example at 20° C. to 120° C.

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is fluorine and an intermediatecompound thereof may be prepared by fluorinating Compound (1) whereinthe substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a),R^(3b), R^(3c) or R^(3d) is bromine or iodine and an intermediatecompound thereof, respectively.

The fluorinating reaction may be carried out by treating Compound (I)which is bromine or iodine or an intermediate compound thereof in anappropriate solvent (e.g., ether such as tetrahydrofuran or aliphatichydrocarbon such as hexane, or a mixture thereof) with alkyllithium(e.g., butyllithium), followed by a fluorinating agent (e.g.,N-fluorobenzenesulfonimide).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is halogen and an intermediatecompound thereof may be prepared by halogenating Compound (I) whereinthe substituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a),R^(3b), R^(3c) or R^(3d) is hydrogen and an intermediate compoundthereof, respectively.

The halogenating reaction may be carried out in an appropriate solvent(e.g., ether such as tetrahydrofuran, amide such asN,N-dimethylformamide, halogenohydrocarbon such as dichloromethane, orcarboxylic acid such as acetic acid, or a mixture thereof) in thepresence of a halogenating agent (e.g., N-halogenosuccinimide).

Compound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl and an intermediatecompound thereof may be prepared by treating Compound (I) wherein thesubstituent group R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b),R^(3c) or R^(3d) is oxo-substituted alkyl and an intermediate compoundthereof, respectively, with hydrazine, followed by reducing theresulting hydrazone.

The treatment with hydrazine may be carried out in an appropriatesolvent (e.g., alcohol such as ethanol) in the presence of hydrazinemonohydrate.

The reduction reaction of hydrazone may be carried out in an appropriatesolvent (e.g., alcohol such as ethylene glycol) in the presence of abase (e.g., alkali metal hydroxide such as potassium hydroxide).

Alternatively, Compound (I) wherein the substituent group R¹, R^(2a),R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is alkyl and anintermediate compound thereof may be prepared by silane-reduction ofCompound (I) wherein the substituent group R¹, R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) is oxo-substituted alkyl and anintermediate compound thereof, respectively. The silane-reduction of theoxo-substituted alkyl may be carried out according to the method of theabove silane-reduction of hydroxy-substituted alkyl.

Compound (I) wherein two substituent groups selected from thesubstituent groups R^(3a), R^(3b), R^(3c) and R^(3d) are two hydrogenson the same carbon atom constituting Ring B and an intermediate compoundthereof may be prepared by hydrazone-reduction or silane-reduction ofCompound (I) wherein two substituent groups selected from thesubstituent group R^(3a), R^(3b), R^(3c) and R^(3d) combine each otherto form oxo and an intermediate compound thereof, respectively.

The hydrazone-reduction or silane-reduction may be carried out accordingto the method of the above reduction of the oxo-substituted alkyl.

Compound (I) wherein the substituent group X is carboxy and anintermediate compound thereof may be prepared by hydrolyzing Compound(I) wherein the substituent group X is alkoxycarbonyl and anintermediate compound thereof, respectively, according to a conventionalmethod.

The hydrolysis may be carried out by treating Compound (I) wherein thesubstituent group X is alkoxycarbonyl or an intermediate compoundthereof with a base (e.g., sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium methoxide and sodium ethoxide) in anappropriate inactive solvent (e.g., tetrahydrofuran, 1,4-dioxane,methanol, ethanol and water, or a mixture thereof).

Compound (I) wherein the substituent group X is hydroxyalkyl and anintermediate compound thereof may be prepared by reacting Compound (I)wherein the substituent group X is alkoxycarbonyl or alkanoyl and anintermediate compound thereof, respectively, with lithium aluminumhydride or alkylmagnesium bromide.

Compound (I) wherein the substituent group X is optionally substitutedaminocarbonyl and an intermediate compound thereof may be prepared byamidating Compound (I) wherein the substituent group X is carboxy oralkoxycarbonyl and an intermediate compound thereof, respectively, withthe corresponding amine according to a conventional method.

[Preparation of Intermediate Compounds]

Compound (IV) may be prepared according to the following Scheme A1.

(In the above Scheme, LG^(A) is a leaving group and includes halogensuch as chlorine, bromine; substituted sulfonyloxy such astrifluoromethylsulfonyloxy, and other symbols are the same as definedabove.)

Compound (A-1) may be aminated to give Compound (A-2). The resultingcompound may be hydrolyzed to give Compound (IV).

The amination of Compound (A-1) may be carried out in an appropriatesolvent (e.g., aromatic hydrocarbon such as toluene) with or without aligand (e.g., phosphine such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in the presence ofbenzophenone imine, palladium catalyst (e.g.,tris(dibenzylideneacetone)dipalladium) and a base (e.g., alkali metalalkoxide such as sodium-t-butoxide). The reaction may be carried out athigh temperature, for example at 80° C. to 140° C.

The hydrolysis of Compound (A-2) may be carried out by treating with anacid (e.g., an inorganic acid such as hydrogen chloride) in anappropriate solvent (e.g., ether such as tetrahydrofuran; water, or amixture thereof). The reaction may be carried out at low temperature,room temperature or high temperature, for example at 0° C. to 60° C.

Compound (IV-1) among Compound (IV) may be prepared according to thefollowing Scheme A2.

(In the above Scheme, symbols are the same as defined above.)

Compound (A-3) may be nitrated to give Compound (A-4). The resultingcompound may be reduced to give Compound (IV-1).

The nitration of Compound (A-3) may be carried out without a solvent inthe presence of a nitrating agent (e.g., potassium nitrate) and an acid(e.g., an inorganic acid such as sulfuric acid). The reaction may becarried out at room temperature or high temperature, for example at 20°C. to 100° C.

The reduction of Compound (A-4) may be carried out in an appropriatesolvent (e.g., alcohol such as ethanol; carboxylic acid such as aceticacid, or a mixture thereof) in the presence of a reducing agent (e.g.,iron (0)). The reaction may be carried out at high temperature, forexample at 60° C. to 120° C.

Compound (IV-2) among Compound (IV) may be prepared according to thefollowing Scheme A3.

(In the above Scheme, symbols are the same as defined above.)

Compound (A-5) may be alkenylated to give Compound (A-6). The resultingnitro compound may be reduced to convert into an amino compound,followed by cyclization to give Compound (IV-2).

The alkenylation of Compound (A-5) may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran) in the presence of thecorresponding phosphonic acid ester (e.g., substituted diethylphosphonate) and a base (e.g., alkali metal alkoxide such aspotassium-t-butoxide). The reaction may be carried out at roomtemperature or high temperature, for example at 20° C. to 100° C.

The reduction of Compound (A-6) may be carried out in an appropriatesolvent (e.g., alcohol such as ethanol) in the presence of a reducingagent (e.g., tin (II) chloride). The reaction may be carried out at hightemperature, for example at 60° C. to 100° C.

The cyclization of the resulting amino compound may be carried out in anappropriate solvent (e.g., alcohol such as ethanol) in the presence of abase (e.g., alkali metal alkoxide such as sodium ethoxide). The reactionmay be carried out at high temperature, for example at 60° C. to 100° C.

Compound (IV-3) among Compound (IV) may be prepared according to thefollowing Scheme A4.

(In the above Scheme, a group:

is benzene or monocyclic aromatic heterocycle; a group:

is bicyclic aromatic heterocycle comprised of (a) pyridine condensedwith benzene; or (b) pyridine condensed with monocyclic aromaticheterocycle; R^(1A) is hydrogen or optionally substituted alkyl; andother symbols are the same as defined above.)

Compound (A-7) may be alkylated to give Compound (A-8). The resultingcompound may be cyclized to give Compound (IV-3) wherein R^(1A) isoptionally substituted alkyl.

Compound (A-7) may be cyclized to give Compound (IV-3) wherein R^(1A) ishydrogen.

The alkylation of Compound (A-7) may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran; alcohol such as ethanol)in the presence of the corresponding halogenoalkyl (e.g., alkyl iodideor alkyl bromide) and a base (e.g., organic lithium such asbutyllithium; or alkali metal alkoxide such as sodium ethoxide). Thereaction may be carried out at low temperature or room temperature, forexample at −80° C. to 20° C.

The cyclization of Compound (A-7) or (A-8) may be carried out in anappropriate solvent (e.g., carboxylic acid such as acetic acid) in thepresence of hydrogen bromide. The reaction may be carried out at lowtemperature or room temperature, for example at −20° C. to 20° C.

Compound (VIII-1) among Compound (VIII) may be prepared according to thefollowing Scheme A5.

(In the above Scheme, E¹, E², G¹ and G² are CH, CH, N⁺O⁻, and N,respectively, or are N⁺O⁻, N, CH and CH, respectively.)

Compound (A-9) may be reduced to give Compound (A-10). The resultingcompound may be converted into pyrrolopyridine to give Compound(VIII-1).

The reduction of Compound (A-9) may be carried out in an appropriatesolvent (e.g., halogenohydrocarbon such as chloroform) in the presenceof a reducing agent (e.g., phosphorus oxychloride). The reaction may becarried out at high temperature, for example at 40° C. to 100° C.

The conversion of Compound (A-10) into pyrrolopyridine may be carriedout in an appropriate solvent (e.g., ether such as tetrahydrofuran) inthe presence of a vinylating agent (e.g., vinyl magnesium bromide). Thereaction may be carried out at low temperature or room temperature, forexample at −40° C. to 20° C.

Compound (VI-1) among Compound (VI) may be prepared according to thefollowing Scheme B1.

(In the above Scheme, LG^(B1) is halogen (particularly, bromine oriodine), R^(B1) is alkyl, and other symbols are the same as definedabove.)

Compound (B-1) may be alkoxycarbonylated to give Compound (B-2). Theresulting compound may be reduced to give Compound (VI-1).

Compound (B-1) may be formylated to give Compound (B-3). The resultingcompound may be reduced to give Compound (VI-1).

Compound (B-4) may be esterified to give Compound (B-2). The resultingcompound may be reduced to give Compound (VI-1).

Compound (B-4) may be also reduced to give Compound (VI-1).

The alkoxycarbonylation of Compound (B-1) may be carried out undercarbon monoxide atmosphere in an appropriate solvent (e.g., amide suchas N,N-dimethylformamide or N,N-dimethylacetamide) with or without aligand (e.g., 1,1′-bis(diphenylphosphino)ferrocene) in the presence ofthe corresponding alcohol (R^(B1)OH), a base (e.g., amine such astriethylamine) and a palladium catalyst (e.g., palladium acetate). Thereaction may be carried out at high temperature, for example at 60° C.to 120° C.

The reduction of Compound (B-2) may be carried out in an appropriatesolvent (e.g., aromatic hydrocarbon such as toluene, xylene; ether suchas tetrahydrofuran, diethyl ether; alcohol such as methanol, ethanol, ora mixture thereof) in the presence of a reducing agent (e.g., lithiumborohydride, sodium borohydride, lithium aluminum hydride,diisobutylaluminum hydride). The reaction may be carried out at lowtemperature or room temperature, for example at −80° C. to 20° C.

The formylation of Compound (B-1) may be carried out by treatingCompound (B-1) with butyllithium, followed by N,N-dimethylformamide, inan appropriate solvent (e.g., ether such as tetrahydrofuran). Thereaction may be carried out at low temperature or room temperature, forexample at −80° C. to 20° C.

The reduction of Compound (B-3) may be carried out according to themethod of the above reduction of Compound (B-2).

The esterification of Compound (B-4) may be carried out in the presenceof thionyl chloride in a solvent of the corresponding alcohol (R^(B1)OH). The reaction may be carried out at low temperature or roomtemperature, for example at −20° C. to 20° C.

Alternatively, the esterification of Compound (B-4) may be carried outin an appropriate solvent (e.g., amide such as N,N-dimethylformamide) inthe presence of the corresponding iodoalkyl (R^(B1)I) and a base (e.g.,alkali metal carbonate such as potassium carbonate). The reaction may becarried out at room temperature or high temperature, for example at 20°C. to 60° C.

The reduction of Compound (B-4) may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran) in the presence of areducing agent (e.g., borane complex such as borane-tetrahydrofurancomplex or borane-dimethylsulfide complex). The reaction may be carriedout at low temperature or room temperature, for example at −20° C. to20° C.

Alternatively, the reduction of Compound (B-4) may be carried out bytreating Compound (B-4) with an activating agent (e.g.,N,N′-carbodiimidazole), followed by a reducing agent (e.g., sodiumborohydride), in an appropriate solvent (e.g., ether such astetrahydrofuran). The reaction may be carried out at low temperature,room temperature or high temperature, for example at −20° C. to 80° C.

Compound (VI-2) among Compound (VI) may be prepared according to thefollowing Scheme B2.

(In the above Scheme, symbols are the same as defined above.)

Compound (B-5) may be formylated to give Compound (B-6). The resultingcompound may be reduced to give Compound (VI-2).

The formylation of Compound (B-5) may be carried out by treatingCompound (B-5) with a base (e.g., alkali metal amide such as lithiumdiisopropylamide), followed by a formylating agent (e.g.,N,N-dimethylformamide), in an appropriate solvent (e.g., ether such astetrahydrofuran). The reaction may be carried out at low temperature orroom temperature, for example at −80° C. to 20° C.

The reduction of Compound (B-6) may be carried out according to themethod of the above reduction of Compound (B-2).

Compound (VI-3) among Compound (VI) may be prepared according to thefollowing Scheme B3.

(In the above Scheme, R^(B2) is alkyl, and other symbols are the same asdefined above.)

Compound (B-7) may be oxidized to give Compound (B-8). The resultingcompound may be cyanated to give Compound (B-9). The resulting compoundmay be reduced to give Compound (B-10). Further, the resulting compoundmay be reduced to give Compound (VI-3).

The oxidization of Compound (B-7) may be carried out in an appropriatesolvent (e.g., halogenohydrocarbon such as dichloromethane) in thepresence of an oxidizing agent (e.g., peroxycarboxylic acid such asmetachloroperoxybenzoic acid). The reaction may be carried out at lowtemperature, room temperature or high temperature, for example at 0° C.to 50° C.

The cyanation of Compound (B-8) may be carried out in an appropriatesolvent (e.g., halogenohydrocarbon such as dichloromethane) in thepresence of a cyanating agent (e.g., tetrabutylammonium cyanide). Thereaction may be carried out at room temperature or high temperature, forexample at 20° C. to 50° C.

The reduction of Compound (B-9) may be carried out in an appropriatesolvent (e.g., ether such as tetrahydrofuran) in the presence of areducing agent (e.g., diisobutylaluminum hydride). The reaction may becarried out at low temperature, for example at −80° C. to 0° C.

The reduction of Compound (B-10) may be carried out according to themethod of the above reduction of Compound (B-2).

Compound (VI-4) among Compound (VI) may be prepared according to thefollowing Scheme B4.

(In the above Scheme, R^(B3) is alkyl, and other symbols are the same asdefined above.)

Compound (B-11) may be converted into benzothiophene to give Compound(B-12). The resulting compound may be reduced to give Compound (VI-4).

Compound (B-12) may be hydrolyzed to give Compound (B-13). The carboxylgroup of the resulting compound may be converted intoN-methoxy-N-methylamide, followed by reduction to give Compound (B-14).The resulting compound may be reduced to give Compound (VI-4).

Compound (B-13) may be reduced to give Compound (VI-4).

The conversion of Compound (B-11) into benzothiophene may be carried outin an appropriate solvent (e.g., amide such as N,N-dimethylformamide) inthe presence of the corresponding thioglycolic acid ester and a base(e.g., alkali metal carbonate such as potassium carbonate). The reactionmay be carried out at high temperature, for example at 40° C. to 80° C.

The reduction of Compound (B-12) may be carried out according to themethod of the above reduction of Compound (B-2).

The hydrolysis of Compound (B-12) may be carried out according to themethod of the above conversion of Compound (I) wherein the substituentgroup X is alkoxycarbonyl and an intermediate compound thereof intoCompound (I) wherein the substituent group X is carboxy and anintermediate compound thereof, respectively.

The conversion of Compound (B-13) into N-methoxy-N-methylamide may becarried out in an appropriate solvent (e.g., halogenohydrocarbon such asdichloromethane, chloroform or dichloroethane) in the presence of anamine (e.g., N,O-dimethylhydroxyamine or N,O-dimethylhydroxyaminehydrochloride) and a base (e.g., an organic base such as triethylamine).The subsequent reduction may be carried out according to the method ofthe above reduction of Compound (B-9).

The reduction of Compound (B-14) may be carried out according to themethod of the above reduction of Compound (B-2).

The reduction of Compound (B-13) into Compound (VI-4) may be carried outaccording to the method of the above reduction of Compound (B-4).

Compound (VI-5) among Compound (VI) may be prepared according to thefollowing Scheme B5.

(In the above Scheme, p is 1 or 2; a group:

is (a) bicyclic aromatic hydrocarbon comprised of benzene condensed withmonocyclic alicyclic hydrocarbon; or (b) bicyclic aromatic heterocyclecomprised of monocyclic aromatic heterocycle condensed with monocyclicalicyclic hydrocarbon; and other symbols are the same as defined above.)

Compound (B-15) may be reduced to give Compound (VI-5).

The reduction of Compound (B-15) may be carried out according to themethod of the above reduction of Compound (B-2).

Alternatively, the reduction of Compound (B-15) may be carried out in anappropriate solvent (e.g., ether such as tetrahydrofuran) with orwithout a catalyst (e.g., boron-containing 5-membered ring compound suchas(2S)-1-(1,3,2-dioxaborolan-2-yloxy)-3-methyl-1,1-diphenylbutan-2-amine)in the presence of a reducing agent (e.g., borane complex such asborane-tetrahydrofuran complex or borane-dimethylsulfide complex). Thereaction may be carried out at low temperature or room temperature, forexample at −40° C. to 20° C.

The protection of amino group may be carried out by converting aminogroup into t-butoxycarbonyl, for example.

The conversion of amino group into t-butoxycarbonyl may be carried outin an appropriate solvent (e.g., halogenohydrocarbon such asdichloromethane) in the presence of di-t-butyl dicarbonate and acatalyst (e.g., N,N-dimethyl-4-aminopyridine).

The removal of t-butylcarbonyl protective group may be carried out bytreating with an acid (e.g., hydrogen chloride or trifluoroacetic acid)in an appropriate solvent (e.g., ether such as tetrahydrofuran) orwithout a solvent.

Alternatively, the removal of t-butylcarbonyl protective group may becarried out in an appropriate solvent (e.g., a mixed solvent of dimethylsulfoxide and water) at high temperature, for example at 100° C. to 150°C.

The protection of hydroxy may be carried out by converting hydroxy intomethoxymethyl, for example.

The conversion of hydroxy into methoxymethyl may be carried out in anappropriate solvent (e.g., halogenohydrocarbon such as dichloromethane)in the presence of chloromethyl methyl ether and a base (e.g., aminesuch as N,N-diisopropylethylamine).

The removal of methoxymethyl protective group may be carried out bytreating with an acid (e.g., hydrogen chloride) in an appropriatesolvent (e.g., a mixed solvent of alcohol such as ethanol and water).

Other starting materials may be commercially available, or may be easilyprepared according to a conventional method known in the art.

The present invention is illustrated by Examples in more detail asfollows, but is not limited thereto.

EXAMPLES

In the following Example section and tables, Me means methyl, Et meansethyl and n-Pr means propyl. And a racemic mixture may be separated by achiral HPLC to give the optically active compounds.

Example 1 Preparation of ethyl4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate

-   (1) To a solution of 4-methylisoquinoline-3-amine (2.00 g, 12.6    mmol) in pyridine (50.6 ml) was added ethyl 4-chlorosulfonylbenzoate    (3.30 g, 13.3 mmol) at room temperature. The mixture was stirred at    80° C. for 3 hours, and then the reaction solution was concentrated    under reduced pressure. The resulting residue was diluted with 2    mol/L hydrochloric acid solution and water, and extracted with ethyl    acetate twice. The organic layer was combined, washed with water and    saturated brine, dried over anhydrous sodium sulfate, and then    concentrated under reduced pressure. The resulting residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=4:1→1:1), and then washed with diisopropyl ether to give    ethyl 4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (4.29 g,    92%) as a pale yellow powder.

APCI-MS m/z:371 [M+H]⁺.

-   (2) To a solution of the above compound (800 mg, 2.16 mmol) in    N,N-dimethylformamide (21.6 ml) were added potassium carbonate (358    mg, 2.59 mmol) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene (427    μl, 2.59 mmol) at room temperature. The mixture was stirred at the    same temperature overnight, and then to the reaction solution was    added water. The mixture was extracted with ethyl acetate twice. The    organic layer was combined, washed with water and saturated brine,    dried over anhydrous sodium sulfate, and then concentrated under    reduced pressure. The resulting residue was purified by silica gel    column chromatography (hexane:ethyl acetate=9:1→3:1) to give ethyl    4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (1.12 g, 95%) as a colorless powder.

APCI-MS m/z:545[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 1.37 (3H, t, J=7.3 Hz), 2.44 (3H, s), 4.39 (2H, q,J=7.3 Hz), 4.45-5.30 (2H, m), 7.20 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.8Hz), 7.74 (1H, t, J=7.3 Hz), 7.81-7.88 (3H, m), 8.05 (1H, d, J=8.5 Hz),8.10-8.18 (3H, m), 9.00 (1H, s).

Example 2 Preparation of sodium4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate

A suspension of ethyl4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate(1.11 g, 2.04 mmol) prepared in Example 1 and 2 mol/L aqueous sodiumhydroxide solution (1.02 ml, 2.04 mmol) in ethanol (20.4 ml) was heatedto reflux for 1 hour. The reaction solution was concentrated underreduced pressure, and the resulting residue is washed with diethyl etherand pentane to give sodium4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate(1.07 g, 94%) as a colorless powder.

ESI-MS m/z:515[M−Na]⁻.

¹H-NMR (DMSO-d₆) δ 2.46 (3H, s), 4.40-5.20 (2H, m), 7.19 (2H, d, J=8.0Hz), 7.30 (2H, d, J=8.7 Hz), 7.58 (2H, d, J=8.3 Hz), 7.72 (1H, t, J=7.1Hz), 7.80-7.85 (1H, m), 7.98 (2H, d, J=8.7 Hz), 8.04 (1H, d, J=8.7 Hz),8.11 (1H, d, J=8.0 Hz), 9.01 (1H, s).

Example 3 Preparation of ethyl4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)-amino]sulfonyl}benzoate

To a solution of ethyl4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (80 mg, 0.22 mmol)obtained in Example 1-(1) and[3-fluoro-4-(trifluoromethoxy)phenyl]methanol (57 mg, 0.27 mmol)obtained in Reference example 1 in tetrahydrofuran (3 ml) was addedtriphenylphosphine (85 mg, 0.32 mmol) at room temperature. The abovesolution was cooled to 0° C., and then thereto was added diisopropylazodicarboxylate (64 μl, 0.32 mmol). The mixture was slowly warmed toroom temperature and stirred at the same temperature overnight. Thereaction solution was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=5:1→2:1) to give ethyl4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(51 mg, 42%) as a white solid.

APCI-MS m/z:563[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 1.36 (3H, t, J=7.0 Hz), 2.50 (3H, s), 4.39 (2H, q,J=7.2 Hz), 4.68-5.01 (2H, m), 7.18 (1H, d, J=8.5 Hz), 7.33 (1H, dd,J=10.9, 1.8 Hz), 7.43 (1H, dd, J=8.5, 8.5 Hz), 7.75 (1H, m), 7.83-7.88(3H, m), 8.09 (1H, d, J=8.5 Hz), 8.13-8.15 (3H, m), 9.01 (1H, s).

Example 4 Preparation of sodium4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)-amino]sulfonyl}benzoate

To a suspension of ethyl4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(47 mg, 0.084 mmol) prepared in Example 3 in ethanol (1 ml) was added 1mol/L aqueous sodium hydroxide solution (167 μl, 0.167 mmol), and themixture was stirred at room temperature overnight. To the reactionsolution was added water (2 ml), and then the solution was acidified by6 mol/L hydrochloric acid solution. The precipitated solid was filtered,washed with water, and then dried at 60° C. under reduced pressure togive a white solid (39.7 mg). The solid was resuspended in ethanol (1ml), and then thereto was added 1 mol/L aqueous sodium hydroxidesolution (73 μl, 0.073 mmol). The mixture was stirred and dissolved, andthen the reaction solution was concentrated under reduced pressure andthe precipitated solid was dried to give sodium4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(42 mg, 89%) as a white solid.

ESI-MS m/z:533[M−Na]⁻.

¹H-NMR (DMSO-d₆) δ 2.52 (3H, s), 4.68 (1H, brs), 4.96 (1H, brs), 7.18(1H, d, J=8.7 Hz), 7.33 (1H, dd, J=11.2, 1.9 Hz), 7.42 (1H, dd, J=8.0,8.0 Hz), 7.73 (1H, m), 7.56 (2H, m), 7.84 (1H, m), 7.97 (2H, m), 8.07(1H, d, J=8.7 Hz), 8.12 (1H, d, J=8.0 Hz), 9.11 (1H, s).

Example 5 Preparation of ethyl4-({(4-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate

-   (1) A mixture of 4,7-dichloro-1-methyl-1H-pyrrolo[2,3-c]pyridine    (153 mg, 760 μmol) obtained in Reference example 2 and    4-(trifluoromethoxy)benzylamine (1.45 g, 7.60 mmol) was stirred at    200° C. for 6 hours under microwave irradiation. After cooling, to    the reaction solution was added 1 mol/L aqueous citric acid    solution, and the mixture was extracted with ethyl acetate twice.    The organic layer was combined, washed with water, filtered through    diatomite column, and then concentrated under reduced pressure. The    resulting residue was purified by silica gel column chromatography    (hexane:ethyl acetate=19:1→1:1) to give    4-chloro-1-methyl-N-[4-(trifluoromethoxy)benzyl]-1H-pyrrolo[2,3-c]pyridine-7-amine    (138 mg, 51%) as a yellow viscous material.

APCI-MS m/z:356/358[M+H]⁺.

-   (2) To a solution of the above compound (136 mg, 381 μmol) in    pyridine (1.91 ml) was added ethyl 4-chlorosulfonylbenzoate (190 mg,    763 μmol) at room temperature, and the mixture was stirred at 80° C.    for 6 hours. Then, thereto was added additional ethyl    4-chlorosulfonylbenzoate (379 mg, 1.53 mmol), and the mixture was    stirred at 80° C. overnight. After cooling, the reaction solution    was diluted with ethyl acetate, washed with 1 mol/L aqueous citric    acid solution, water, saturated aqueous sodium hydrogen carbonate    solution and saturated brine, dried over anhydrous sodium sulfate,    and then concentrated under reduced pressure. The resulting residue    was purified by silica gel column chromatography (hexane:ethyl    acetate=19:1→4:1) to give ethyl    4-({(4-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (51.1 mg, 24%) as a pale yellow viscous material.

APCI-MS m/z:568/570[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 1.37 (3H, t, J=7.3 Hz), 3.87 (3H, s), 4.39 (2H, q,J=7.3 Hz), 4.59 (1H, d, J=13.0 Hz), 5.07 (1H, d, J=13.0 Hz), 6.56 (1H,d, J=3.0 Hz), 7.20 (2H, d, J=8.0 Hz), 7.25 (2H, d, J=8.8 Hz), 7.66 (2H,d, J=3.0 Hz), 7.85 (1H, d, J=8.5 Hz), 7.97 (1H, s), 8.16 (2H, d, J=8.5Hz).

Example 6 Preparation of sodium4-({(4-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate

Ethyl4-({(4-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(50.7 mg, 89.3 μmol) prepared in Example 5 was treated in a similarmanner to Example 2 to give sodium4-({(4-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate(49.4 mg, 98%) as a colorless powder.

ESI-MS m/z:538/540[M−Na]⁻.

¹H-NMR (DMSO-d₆) δ 3.90 (3H, s), 4.58 (1H, d, J=13.2 Hz), 4.99 (1H, d,J=13.2 Hz), 6.54 (1H, d, J=3.2 Hz), 7.20 (2H, d, J=8.0 Hz), 7.25 (2H, d,J=8.7 Hz), 7.53 (2H, d, J=8.3 Hz), 7.64 (1H, d, J=2.9 Hz), 7.96-8.00(3H, m).

Example 7 Preparation of ethyl4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoate

-   (1) Ethyl 4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    obtained in Example 1-(1) and 1-bromo-4-(bromomethyl)benzene were    treated in a similar manner to Example 1-(2) to give ethyl    4-{[(4-bromobenzyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (469 mg, 79%) as a colorless powder.

APCI-MS m/z:539[M+H]⁺.

-   (2) To a mixed solution of the above compound (110 mg, 0.2 mmol),    4-fluorophenylboric acid (33 mg, 0.22 mmol) and    tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol) in    1,2-dimethoxyethane (2.0 ml) and water (1.0 ml) was added sodium    carbonate (33 mg, 0.3 mmol), and the mixture was heated to reflux    for 6 hours. To the reaction solution was added water, and the    mixture was extracted with ethyl acetate twice. The organic layer    was combined, washed with water and saturated brine, dried over    anhydrous sodium sulfate, and then concentrated under reduced    pressure. The resulting residue was purified by silica gel column    chromatography (hexane:ethyl acetate=9:1→3:1) to give ethyl    4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (88.0 mg, 78%) as a colorless powder.

Example 8 Preparation of4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid

A suspension of ethyl4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(88.0 mg, 0.16 mmol) prepared in Example 7 and 1 mol/L aqueous sodiumhydroxide solution (320 μl, 0.32 mmol) in methanol (1.6 ml) was stirredat room temperature overnight, and then to the reaction solution wasadded 2 mol/L hydrochloric acid solution (400 μl). The mixture wasextracted with chloroform twice. The organic layer was combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography(chloroform:methanol=10:0→9:1) to give4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid (62.1 mg, 74%) as a colorless powder.

APCI-MS m/z:527[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 2.49 (3H, s), 4.50-5.15 (2H, m), 7.19-7.28 (4H, m),7.50 (2H, d, J=8.4 Hz), 7.58-7.63 (2H, m), 7.70-7.74 (1H, m), 7.80-7.86(3H, m), 8.03-8.06 (1H, m), 8.11-8.15 (3H, m), 9.01 (1H, s).

Example 9 Preparation of ethyl4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate

-   (1) 1-Bromo-4-methylisoquinoline-3-amine, ethyl    4-chlorosulfonylbenzoate and    1-(bromomethyl)-4-(trifluoromethoxy)benzene were treated in a    similar manner to Examples 1-(1) and (2) to give ethyl    4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate    as a colorless solid.

APCI-MS m/z:623/625 [M+H]⁺.

-   (2) A mixture of the above compound (100 mg, 160 μmol), potassium    cyclopropyltrifluoroborate (45.9 mg, 321 μmol), palladium acetate    (3.7 mg, 16.0 μmol), di(1-adamantyl)butylphosphine (9.1 mg, 24.1    μmol), cesium carbonate (105 mg, 321 μmol), water (80 μl) and    toluene (802 μl) was heated to reflux under argon atmosphere for 3    hours. After cooling, the reaction solution was diluted with ethyl    acetate, filtered through diatomite column, and then concentrated    under reduced pressure. The resulting residue was purified by silica    gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give    ethyl    4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (93.0 mg, 99%) as a pale yellow solid.

APCI-MS m/z:585[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 0.25-0.95 (4H, m), 1.37 (3H, t, J=7.3 Hz), 2.38 (3H,s), 2.73-2.82 (1H, m), 4.40 (2H, q, J=7.3 Hz), 4.46-5.12 (2H, m), 7.20(2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.8 Hz), 7.69-7.75 (1H, m), 7.77-7.84(3H, m), 8.01 (1H, d, J=8.2 Hz), 8.14 (2H, d, J=8.5 Hz), 8.49 (1H, d,J=8.2 Hz).

Example 10 Preparation of sodium4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate

A mixture of ethyl4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(92.0 mg, 157 μmol) prepared in Example 9, 2 mol/L aqueous sodiumhydroxide solution (79 μl, 157 μmol) and ethanol (1.57 ml) was heated toreflux for 1 hour. The reaction solution was concentrated under reducedpressure, and the resulting residue was washed with diethyl ether andpentane to give sodium4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate(86.6 mg, 95%) as a colorless powder.

ESI-MS m/z:555[M−Na]⁻.

¹H-NMR (DMSO-d₆) δ 0.45-0.95 (4H, m), 2.41 (3H, s), 2.76-2.83 (1H, m),4.40-5.10 (2H, m), 7.19 (2H, d, J=8.0 Hz), 7.27 (2H, d, J=8.7 Hz), 7.53(2H, d, J=8.7 Hz), 7.68-7.73 (1H, m), 7.77-7.82 (1H, m), 7.97-8.02 (3H,m), 8.49 (1H, d, J=8.3 Hz).

Example 11 Preparation of ethyl4-{[{[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]methyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate

-   (1) Ethyl 4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    obtained in Example 1-(1) and    6-(bromomethyl)-3-fluoro-2-iodopyridine obtained in Reference    example 3 were treated in a similar manner to Example 1-(2) to give    ethyl    4-{[[(5-fluoro-6-iodopyridin-2-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    as a colorless viscous material.

APCI-MS m/z:606[M+H]⁺.

-   (2) To a mixed solution of the above compound (68 mg, 0.112 mmol) in    N,N-dimethylformamide (0.5 mL) and hexamethylphosphoric triamide    (0.5 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate    (104 μL, 0.82 mmol) and copper (I) iodide (156 mg, 0.82 mmol) at    room temperature under argon atmosphere. The reaction solution was    stirred at 70° C. overnight, cooled to room temperature, and then to    the reaction solution was added water. The mixture was extracted    with ethyl acetate twice. The organic layer was combined, washed    with water and saturated brine, dried over anhydrous sodium sulfate,    and then concentrated under reduced pressure. The resulting residue    was purified by silica gel column chromatography (hexane:ethyl    acetate=17:3→3:2) to give ethyl    4-{[{[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]methyl}(4-methylisoquinolin-3-yl)-amino]sulfonyl}benzoate    (41 mg, 68%) as a colorless powder.

APCI-MS m/z:548[M+H]⁺.

¹H-NMR (CDCl₃) δ 1.43 (3H, t, J=7.3 Hz), 2.73 (3H, s), 4.44 (2H, q,J=7.3 Hz), 5.02 (2H, s), 7.44-7.49 (1H, m), 7.63-7.66 (1H, m), 7.73-7.76(2H, m), 7.78 (2H, d, J=8.5 Hz), 7.93 (1H, d, J=8.3 Hz), 8.03 (1H, d,J=8.3 Hz), 8.16 (2H, d, J=8.5 Hz), 8.82 (1H, s).

Example 12 Preparation of sodium4-{[{[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]methyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate

Ethyl4-{[{[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]methyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(38 mg, 0.64 mmol) prepared in Example 11 was treated in a similarmanner to Example 2 to give sodium4-{[{[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]methyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(35 mg, 93%) as a colorless powder.

ESI-MS m/z:518[M−Na]⁻.

¹H-NMR (DMSO-d₆) δ 2.61 (3H, s), 4.85 (1H, brs), 5.10 (1H, brs), 7.55(2H, d, J=8.7 Hz), 7.70-7.74 (1H, m), 7.77-7.79 (1H, m), 7.83-7.86 (1H,m), 7.92-7.95 (1H, m), 7.96 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.7 Hz),8.97 (1H, s).

Example 13 Preparation of ethyl4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate

-   (1) Ethyl 4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    obtained in Example 1-(1) and    4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzylalcohol were    treated in a similar manner to Example 3 to give ethyl    4-({(4-methylisoquinolin-3-yl)[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzyl]amino}sulfonyl)benzoate    as a colorless viscous material.

APCI-MS m/z:573[M+H]⁺.

-   (2) To a solution of the above compound (100 mg, 0.18 mmol) in    N,N-dimethylformamide (2 ml) was added sodium hydride (10.5 mg, 0.26    mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and    then thereto was added iodoethane (42 μl, 0.52 mmol) at the same    temperature. The mixture was stirred at room temperature overnight,    and then to the reaction solution was added water. The mixture was    extracted with ethyl acetate three times. The organic layer was    combined, washed with water twice, dried over anhydrous sodium    sulfate, and then concentrated under reduced pressure. The resulting    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=10:0→7:3) to give ethyl    4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (103 mg, 98%) as a colorless liquid.

APCI-MS m/z:601[M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.00-1.13 (3H, m), 1.37 (3H, t, J=7.0 Hz),1.66 (3H, s), 2.39 (3H, s), 2.89-3.05 (1H, m), 3.29-3.41 (1H, m), 4.39(2H, q, J=7.0 Hz), 4.48-5.16 (2H, m), 7.22 (2H, d, J=8.5 Hz), 7.34 (2H,d, J=8.2 Hz), 7.73 (1H, t, J=7.3 Hz), 7.82 (1H, d, J=8.5 Hz), 7.86 (2H,d, J=8.5 Hz), 8.03 (1H, d, J=8.5 Hz), 8.12-8.15 (3H, m), 9.11 (1H, s).

Example 14 Preparation of4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid

To a mixed solution of ethyl4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(102 mg, 0.17 mmol) prepared in Example 13 in ethanol (1 mL) andtetrahydrofuran (1 mL) was added 2 mol/L aqueous sodium hydroxidesolution (340 μL, 0.68 mmol) at room temperature. The reaction solutionwas stirred at room temperature overnight, and then to the reactionsolution was added 2 mol/L hydrochloric acid solution (1 ml). Themixture was extracted with chloroform three times. The organic layer wascombined, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (chloroform:methanol=10:0→10:1) to give4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid (82 mg, 85%) as a colorless powder.

APCI-MS m/z:573[M+H]⁺.

¹H-NMR (DMSO-d₆) δ 1.00-1.14 (3H, m), 1.66 (3H, s), 2.39 (3H, s),2.89-3.05 (1H, m), 3.17-3.51 (1H, m), 4.49-5.28 (2H, m), 7.22 (2H, d,J=8.5 Hz), 7.34 (2H, d, J=8.2 Hz), 7.73 (1H, t, J=7.3 Hz), 7.81-7.85(3H, m), 8.03 (1H, d, J=8.8 Hz), 8.11-8.14 (3H, m), 9.02 (1H, s),12.71-14.59 (1H, m).

Examples 15 to 37

The corresponding starting compounds were treated in a similar manner toExamples 1, 2 and/or 8 to give the following compounds of Table 1.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 1 Example Structure Physical data 15

solid APCI-MS m/z: 531[M + H]⁺ 16

solid APCI-MS m/z: 545[M + H]⁺ 17

solid ESI-MS m/z: 515[M − H]⁻ 18

powder APCI-MS m/z: 533[M + H]⁺ 19

powder APCI-MS m/z: 547[M + H]⁺ 20

powder ESI-MS m/z: 517[M − H]⁻ 21

powder APCI-MS m/z: 461[M + H]⁺ 22

powder ESI-MS m/z: 431[M − Na]⁻ 23

powder APCI-MS m/z: 489[M + H]⁺ 24

powder APCI-MS m/z: 487[M + H]⁺ 25

powder APCI-MS m/z: 535[M + H]⁺ 26

powder APCI-MS m/z: 507[M + H]⁺ 27

powder APCI-MS m/z: 509[M + H]⁺ 28

powder APCI-MS m/z: 525[M + H]⁺ 29

powder APCI-MS m/z: 547[M + H]⁺ 30

powder ESI-MS m/z: 517[M − Na]⁻ 31

powder APCI-MS m/z: 483[M + H]⁺ 32

powder APCI-MS m/z: 483[M + H]⁺ 33

powder APCI-MS m/z: 575[M + H]⁺ 34

powder ESI-MS m/z: 545[M − Na]⁻ 35

powder ESI-MS m/z: 535/537[M − Na]⁻ 36

powder APCI-MS m/z: 533[M + H]⁺ 37

powder ESI-MS m/z: 503[M − Na]⁻

Examples 38 to 87

The corresponding starting compounds were treated in a similar manner toExamples 3, 4 and/or 8 to give the following compounds of Table 2.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 2 Example Structure Physical data 38

powder APCI-MS m/z: 477[M + H]⁺ 39

powder APCI-MS m/z: 573[M + H]⁺ 40

solid APCI-MS m/z: 545[M + H]⁺ 41

powder APCI-MS m/z: 473[M + H]⁺ 42

powder ESI-MS m/z: 501[M − Na]⁺ 43

powder ESI-MS m/z: 515[M − Na]⁻ 44

powder ESI-MS m/z: 529[M − Na]⁻ 45

powder APCI-MS m/z: 489[M + H]⁺ 46

powder APCI-MS m/z: 517[M + H]⁺ 47

powder APCI-MS m/z: 510[M + H]⁺ 48

solid APCI-MS m/z: 510[M + H]⁺ 49

powder APCI-MS m/z: 525[M + H]⁺ 50

powder APCI-MS m/z: 525[M + H]⁺ 51

powder ESI-MS m/z: 519[M − Na]⁻ 52

powder ESI-MS m/z: 535/537[M − Na]⁻ 53

solid APCI-MS m/z: 501[M + H]⁺ 54

solid APCI-MS m/z: 473[M + H]⁺ 55

solid APCI-MS m/z: 473[M + H]⁺ 56

powder APCI-MS m/z: 487[M + H]⁺ 57

solid APCI-MS m/z: 459[M + H]⁺ 58

solid APCI-MS m/z: 459[M + H]⁺ 59

viscous material APCI-MS m/z: 501[M + H]⁺ 60

solid APCI-MS m/z: 473[M + H]⁺ 61

powder APCI-MS m/z: 501[M + H]⁺ 62

powder APCI-MS m/z: 501[M + H]⁺ 63

powder APCI-MS m/z: 553[M + H]⁺ 64

powder ESI-MS m/z: 523[M − Na]⁻ 65

powder APCI-MS m/z: 530[M + H]⁺ 66

powder APCI-MS m/z: 502[M + H]⁺ 67

powder APCI-MS m/z: 510[M + H]⁺ 68

solid APCI-MS m/z: 540/542[M + H]⁺ 69

powder ESI-MS m/z: 510/512[M − Na]⁻ 70

solid APCI-MS m/z: 510[M + H]⁺ 71

powder APCI-MS /z: 500[M + H]⁺ 72

powder ESI-MS m/z: 470[M − Na]⁻ 73

powder APCI-MS m/z: 534/536[M + H]⁺ 74

powder ESI-MS m/z: 504/506[M − Na]⁻ 75

powder ESI-MS m/z: 504/506[M − Na]⁻ 76

powder APCI-MS m/z: 549/551[M + H]⁺ 77

powder ESI-MS m/z: 518/520[M − Na]⁻ 78

powder ESI-MS m/z: 518/520[M − Na]⁻ 79

powder APCI-MS m/z: 503[M + H]⁺ 80

powder APCI-MS m/z: 503[M + H]⁺ 81

powder APCI-MS m/z: 503[M + H]⁺ 82

powder ESI-MS m/z: 501[M − Na]⁻ 83

powder APCI-MS m/z: 503[M + H]⁺ 84

powder ESI-MS m/z: 487[M − Na]− 85

solid APCI-MS m/z: 516[M + H]⁺ 86

powder APCI-MS m/z: 522[M + H]⁺ 87

powder ESI-MS m/z: 492[M − Na]⁻

Examples 88 to 91

The corresponding starting compounds were treated in a similar manner toExamples 7, 8 and/or 2 to give the following compounds of Table 3.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 3 Example Structure Physical data 88

solid APCI-MS m/z: 527[M + H]⁺ 89

solid APCI-MS m/z: 527[M + H]⁺ 90

powder APCI-MS m/z: 502[M + H]⁺ 91

powder ESI-MS m/z: 472[M − Na]⁻

Examples 92 to 95

The corresponding starting compounds were treated in a similar manner toExamples 9 and/or 10 to give the following compounds of Table 4.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 4 Example Structure Physical data 92

Powder APCI-MS m/z: 559[M + H]⁺ 93

powder ESI-MS m/z: 529[M − Na]⁻ 94

powder APCI-MS m/z: 621[M + H]⁺ 95

powder ESI-MS m/z: 591[M − Na]⁻

Example 96

The corresponding starting compound was treated in a similar manner toExamples 13 and 14 to give the following compound of Table 5.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 5 Ex- am- Physical ple Structure data 96

solid APCI-MS m/z: 559 [M + H]⁺

Example 97 Preparation of4-({(4-methyl-1-propylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoicacid

-   (1) Ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)    [4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (93.5 mg, 0.15    mmol) prepared in Example 9-(1) and 1-propenylboric acid were    treated in a similar manner to Example 7-(2) to give ethyl    4-({{4-methyl-1-[(1E)-prop-1-en-1-yl]isoquinolin-3-yl}[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (86.9 mg, 99%) as a pale yellow viscous material.

APCI-MS m/z:585 [M+H]⁺

-   (2) To a solution of the above compound (86.9 mg, 0.149 mmol) in    tetrahydrofuran (5 mL) was added platinum oxide (3.4 mg, 0.0149    mmol), and the mixture was stirred under hydrogen atmosphere at room    temperature for 3 hours and filtered through diatomaceous earth    using ethyl acetate. The filtrate was concentrated under reduced    pressure to give a crude ethyl    4-({(4-methyl-1-propylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate.-   (3) The crude product was treated in a similar manner to Example 14    to give    4-({(4-methyl-1-propylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic    acid (70.3 mg, 84%, yields for two steps) as a white powder.

APCI-MS m/z:559[M+H]⁺

Example 98 Preparation of ethyl4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate

A mixture of ethyl4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(93.5 mg, 0.15 mmol) prepared in Example 9-(1), pyrrolidine (0.015 mL,0.18 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.3 mg, 0.015mmol), trisdibenzylideneacetone dipalladium (6.9 mg, 0.0075 mmol) andsodium-t-butoxide (20.2 mg, 0.21 mmol) in toluene (2 mL) was stirred at100° C. for 4 hours under argon atmosphere. The mixture was cooled toroom temperature, and then filtered, and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=10%→25%) to give ethyl4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (22.4 mg, 24%) as ayellow viscous material.

APCI-MS: m/z 614[M+H]⁺

Example 99 Preparation of4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoic acid

Ethyl4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate(22.4 mg, 0.0365 mmol) prepared in Example 98 was treated in a similarmanner to Example 14 to give4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid (20.8 mg, 97%) as a yellow powder.

APCI-MS: m/z 586[M+H]⁺

Example 100 Preparation of 4-({(1-isopropoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoic acid

To a suspension of ethyl4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(93.5 mg, 0.15 mmol) prepared in Example 9-(1) and sodium hydride (60.0mg, 1.5 mmol) in tetrahydrofuran (2 mL) was added 2-propanol (0.115 mL,1.5 mmol) under argon atmosphere, and the mixture was heated to refluxfor 4 hours. The mixture was neutralized by 2 mol/L hydrochloric acid,and then thereto was added chloroform. The mixture was stirred, and thenseparated. The organic layer was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(methanol/chloroform=2%→10%) to give4-({(1-isopropoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (53.1 mg, 58%)as a brown powder.

APCI-MS: m/z 575 [M+H]⁺

Example 101 Preparation of isopropyl4-({(5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate

-   (1) 1-Bromo-5-chloroisoquinolin-3-amine (258 mg, 1 mmol) obtained in    Reference example 21, ethyl 4-chlorosulfonylbenzoate and    1-(bromomethyl)-4-(trifluoromethoxy)benzene were treated in a    similar manner to Examples 1-(1) and (2) to give ethyl    4-({(1-bromo-5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoate    as a brown solid.

APCI-MS: m/z 643/645/647 [M+H]⁺

-   (2) A mixture of the above compound (193 mg, 0.3 mmol), palladium    acetate (3.4 mg, 0.015 mmol), triphenylphosphine (15.7 mg, 0.06    mmol) and potassium carbonate (82.9 mg, 0.6 mmol) in 2-propanol (2    mL) was heated to reflux for 6 hours under argon atmosphere. The    reaction solution was cooled to room temperature, and thereto was    added ethyl acetate. The mixture was filtered, and the insoluble was    removed. The filtrate was concentrated under reduced pressure, and    then purified by silica gel column chromatography (ethyl    acetate/hexane=10%→30%) to give isopropyl    4-({(5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate    (81.2 mg, 47%) as a pale yellow viscous material.

APCI-MS: m/z 579/581 [M+H]⁺

Example 102 Preparation of4-({(5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoicacid

Isopropyl 4-({(5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoate (42.2 mg, 0.0729mmol) prepared in Example 101 was treated in a similar manner to Example14 to give4-({(5-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoicacid (35.8 mg, 91%) as a white powder.

APCI-MS: m/z 537/539 [M+H]⁺

Example 103 Preparation of ethyl4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate

A mixture of ethyl4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate(65.0 mg, 0.107 mmol) prepared in Example 153, cyclopropylboronic acid(27.0 mg, 0.321 mmol), palladium acetate (2.5 mg, 0.011 mmol),tricyclohexylphosphine (5.9 mg, 0.021 mmol) and tripotassium phosphate(79.0 mg, 0.375 mmol) in water (0.027 mL) and toluene (0.54 mL) wasstirred under argon atmosphere at 100° C. for 5 hours. After cooling,the reaction solution was diluted with ethyl acetate, washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=95:5→65:35) togive ethyl4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate(46.7 mg, 78%) as a white powder.

APCI-MS m/z:571[M+H]⁺.

Example 104 Preparation of 4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoic acid

Ethyl 4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (46.0 mg, 0.081mmol) prepared in Example 103 was treated in a similar manner to Example14 to give 4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (41.1 mg, 91%)as a white powder.

APCI-MS m/z:543[M+H]⁺.

Example 105 Preparation of ethyl4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoate

-   (1) Isoquinoline-3-amine and ethyl 4-chlorosulfonylbenzoate were    treated in a similar manner to Example 1-(1) to give ethyl    4-[(isoquinolin-3-ylamino)sulfonyl]benzoate as a white powder.

APCI-MS m/z:357[M+H]⁺.

-   (2) A mixture of the above compound (356.0 mg, 1.00 mmol) and    N-iodosuccinimide (337.0 mg, 1.50 mmol) in acetic acid (5 mL) was    stirred under argon atmosphere at 80° C. for 8 hours. The reaction    solution was cooled, and then concentrated under reduced pressure.    The residue was diluted with ethyl acetate, washed with aqueous    sodium hydrogen carbonate solution and saturated brine, and then    dried over anhydrous sodium sulfate, and then concentrated under    reduced pressure. The resulting residue was purified by silica gel    column chromatography (hexane:ethyl acetate=19:1→3:2) to give ethyl    4-{[(4-iodoisoquinolin-3-yl)amino]sulfonyl}benzoate (250.0 mg, 52%)    as a pale red powder.

APCI-MS m/z:483[M+H]⁺.

-   (3) The above compound (96.0 mg, 0.20 mmol) was treated in a similar    manner to Example 1-(2) to give ethyl    4-({(4-iodoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate    (122.0 mg, 93%) as a white powder.

APCI-MS m/z:657 [M+H]⁺.

-   (4) The above compound (116.0 mg, 0.18 mmol) was treated in a    similar manner to Example 11-(2) to give ethyl    4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoate    (95.0 mg, 90%) as a white powder.

APCI-MS m/z:599[M+H]⁺.

Example 106 Preparation of4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}-sulfonyl)benzoicacid

Ethyl4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}-sulfonyl)benzoate(93.0 mg, 0.16 mmol) prepared in Example 105 was treated in a similarmanner to Example 14 to give4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoicacid (77.7 mg, 88%) as a white powder.

APCI-MS m/z:571[M+H]⁺.

Example 107 Preparation of ethyl4-({[4-methyl-1-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate

-   (1) Ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)    [4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (93.5 mg, 0.15    mmol) prepared in Example 9-(1) was treated in a similar manner to    Reference example 3 to give ethyl    4-({(1-iodo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (73.7 mg, 73%) as a white solid.

APCI-MS: m/z 671 [M+H]⁺

-   (2) The above compound (73.7 mg, 0.11 mmol) was treated in a similar    manner to Example 11-(2) to give ethyl    4-({[4-methyl-1-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (52.7 mg, 78%) as a white solid.

APCI-MS: m/z 613 [M+H]⁺

Example 108 Preparation of4-({[4-methyl-1-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoicacid

Ethyl4-({[4-methyl-1-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate(52.7 mg, 0.086 mmol) prepared in Example 107 was treated in a similarmanner to Example 14 to give4-({[4-methyl-1-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid (47.8 mg, 95%) as a white powder.

APCI-MS: m/z 585 [M+H]⁺

Example 109 Preparation of ethyl4-({[1-isopropyl-4-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate

-   (1) 4-Iodo-1-isopropylisoquinolin-3-amine obtained in Reference    example 25, ethyl 4-chlorosulfonylbenzoate and    1-(bromomethyl)-4-(trifluoromethoxy)benzene were treated in a    similar manner to Examples 1-(1) and (2) to give ethyl    4-({(4-iodo-1-isopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    as a white powder.

APCI-MS m/z:699 [M+H]⁺.

-   (2) The above compound was treated in a similar manner to Example    11-(2) to give ethyl    4-({[1-isopropyl-4-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate    as a white powder.

APCI-MS m/z:641 [M+H]⁺.

Example 110 Preparation of4-({[1-isopropyl-4-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoicacid

Ethyl4-({[1-isopropyl-4-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoateprepared in Example 109 was treated in a similar manner to Example 14 togive4-({[1-isopropyl-4-(trifluoromethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid as a white powder.

APCI-MS m/z:613 [M+H]⁺.

Example 111 Preparation of ethyl 4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate

A mixture of ethyl4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate(122.0 mg, 0.20 mmol) prepared in Example 153,tributyl(1-ethoxyvinyl)tin (94.0 mg, 0.26 mmol) anddichlorobis(triphenylphosphine)palladium (II) (14.0 mg, 0.02 mmol) in1,4-dioxane (1 mL) was heated to reflux under argon atmosphere for 16hours. After cooling, the reaction solution was diluted with ethylacetate, and poured into aqueous potassium fluoride solution. Themixture was stirred for 6 hours. The insoluble was filtered off, andthen the filtrate was extracted with ethyl acetate. The organic layerwas washed with water. Then, thereto was added 2 mol/L hydrochloricacid, and the mixture was stirred for 3 days. Then, the organic layerwas separated, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=19:1→3:2) to give ethyl4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (53.4 mg, 47%) as awhite powder.

APCI-MS m/z:573[M+H]⁺.

Example 112 Preparation of 4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic acid

Ethyl4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoate(51.0 mg, 0.089 mmol) prepared in Example 111 was treated in a similarmanner to Example 14 to give4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoicacid (36.9 mg, 76%) as a white powder.

APCI-MS m/z:545[M+H]⁺.

Example 113 Preparation of4-({[4-(1-hydroxyethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoicacid

To a solution of4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoicacid (20.0 mg, 0.036 mmol) prepared in Example 112 in ethanol (1 mL) wasadded sodium borohydride (10.0 mg, 0.264 mmol), and the mixture wasstirred at room temperature for 3 hours. To the reaction solution wasadded 1 mol/L hydrochloric acid. The reaction solution was concentratedunder reduced pressure, and then diluted with ethyl acetate, washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (chloroform:methanol=10:0→9:1) togive4-({[4-(1-hydroxyethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid (17.1 mg, 87%) as a white powder.

APCI-MS m/z:547[M+H]⁺.

Example 114 Preparation of ethyl4-({[1-(1-hydroxyethyl)-4-methylisoquinolin-3-yl][4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate

-   (1) A mixture of ethyl    4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate    (93.5 mg, 0.15 mmol) prepared in Example 9-(1),    tributyl(1-ethoxyvinyl)tin (0.061 mL, 0.18 mmol) and    dichlorobis(triphenylphosphine)palladium (II) (5.3 mg, 0.0075 mmol)    in 1,4-dioxane (2 mL) was stirred at 80° C. for 4 hours under argon    atmosphere. The reaction solution was concentrated under reduced    pressure, and the residue was purified by silica gel chromatography    (ethyl acetate:hexane=1:9→3:7) to give a crude ethyl    4-({[1-(1-ethoxyvinyl)-4-methyl    isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate    (152 mg) as a pale yellow viscous material.-   (2) To a solution of the above crude product in tetrahydrofuran (5    mL) was added 6 mol/L hydrochloric acid (0.5 mL), and the mixture    was stirred at room temperature for 24 hours. The reaction solution    was diluted with water, and then extracted with ethyl acetate three    times. The organic layer was combined, washed with saturated aqueous    sodium hydrogen carbonate solution, dried over anhydrous sodium    sulfate, and then concentrated under reduced pressure to give a    crude ethyl    4-({(1-acetyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate.-   (3) To a solution of the above crude product in ethanol (5 mL) was    added sodium borohydride (11.3 mg, 0.3 mmol) at 0° C., and the    mixture was stirred at the same temperature for 30 minutes. Then,    thereto was added saturated aqueous ammonium chloride solution, and    the mixture was concentrated under reduced pressure to remove    ethanol, and then extracted with ethyl acetate three times. The    organic layer was dried over anhydrous sodium sulfate, and then    concentrated under reduced pressure. The resulting residue was    purified by silica gel column chromatography (ethyl    acetate:hexane=1:3→1:1) to give ethyl    4-({[1-(1-hydroxyethyl)-4-methylisoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate    (83.0 mg, 94%, yields for three steps) as a colorless viscous    material.

APCI-MS: m/z 589 [M+H]⁺

Example 115 Preparation of4-({[1-(1-hydroxyethyl)-4-methylisoquinolin-3-yl][4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoicacid

Ethyl4-({[1-(1-hydroxyethyl)-4-methylisoquinolin-3-yl][4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate(83.0 mg, 0.141 mmol) prepared in Example 114 was treated in a similarmanner to Example 14 to give4-({[1-(1-hydroxyethyl)-4-methylisoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid (76.0 mg, 96%) as a white powder.

APCI-MS: m/z 561 [M+H]⁺

Example 116 Preparation of ethyl4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}-benzoate

-   (1) tert-Butyl 6-(hydroxymethyl)-1H-indole-1-carboxylate (770 mg,    3.1 mmol) and ethyl    4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (887 mg, 2.4    mmol) obtained in Example 1-(1) were treated in a similar manner to    Example 3 to give tert-butyl    6-{[{[4-(ethoxycarbonyl)phenyl]sulfonyl}(4-methylisoquinolin-3-yl)amino]methyl}-1H-indole-1-carboxylate    (789 mg, 55%) as a colorless oil.

APCI-MS: m/z 600 [M+H]⁺

-   (2) To a solution of the above compound (789 mg, 1.32 mmol) in    dimethyl sulfoxide (5.2 mL) was added water (2.6 mL) at room    temperature, and the mixture was stirred at 120° C. for 5 hours. The    reaction solution was cooled to room temperature, and then thereto    was added water. The mixture was extracted with ethyl acetate twice.    The organic layer was combined, washed with saturated brine, dried    over anhydrous sodium sulfate, and then concentrated under reduced    pressure. The resulting residue was purified by silica gel column    chromatography (hexane:ethyl acetate=19:1→2:1) to give ethyl    4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (535 mg, 81%) as a white solid.

APCI-MS: m/z 500 [M+H]⁺

Example 117 Preparation of4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid

Ethyl4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(62 mg, 0.13 mmol) prepared in Example 116 was treated in a similarmanner to Example 8 to give4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid (28 mg, 48%) as a white solid.

APCI-MS: m/z 472 [M+H]⁺

Example 118 Preparation of ethyl4-{[[(1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoate

-   (1) (1-Methyl-2,3-dihydro-1H-indol-6-yl)methanol (245 mg, 1.50 mmol)    obtained in Reference example 52 and ethyl    4-{[(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (427 mg, 1.15    mmol) obtained in Example 1-(1) were treated in a similar manner to    Example 3 to give ethyl    4-{[[(1-methyl-2,3-dihydro-1H-indol-6-yl)methyl]    (4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (127 mg, 21%) as a    white solid.

APCI-MS: m/z 516 [M+H]⁺

-   (2) To a solution of the above compound (125 mg, 0.24 mmol) in    1,4-dioxane (12 mL) was added    2,3-dichloro-5,6-dicyano-p-benzoquinone (61 mg, 0.26 mmol) at room    temperature, and the mixture was stirred at the same temperature for    3 days. To the reaction solution was added saturated aqueous sodium    bicarbonate solution, and the mixture was stirred for 3 hours, and    then filtered through diatomaceous earth. The insoluble was filtered    off. The filtrate was extracted with ethyl acetate twice. The    organic layer was combined, washed with saturated brine, dried over    anhydrous sodium sulfate, and then concentrated under reduced    pressure. The resulting residue was purified by silica gel column    chromatography (hexane:ethyl acetate=9:1→3:1) to give ethyl    4-{[[(1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (87 mg, 70%) as a white solid.

APCI-MS: m/z 514 [M+H]⁺

Example 119 Preparation of4-{[[(1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid

Ethyl4-{[[(1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoate(83 mg, 0.16 mmol) prepared in Example 118 was treated in a similarmanner to Example 8 to give4-{[[(1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid (65 mg, 83%) as a white solid.

MS: 486 [M+H]⁺, APCI

Example 120 Preparation of ethyl4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoate

To a solution of ethyl4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate(177 mg, 0.36 mmol) prepared in Example 116 in tetrahydrofuran (1.8 mL)was added N-chlorosuccinimide (57 mg, 0.43 mmol) at room temperature,and the mixture was stirred for 17 hours. The reaction solution wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=5:1→1:1) to give ethyl 4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (124 mg, 65%) as awhite solid.

APCI-MS: m/z 534/536 [M+H]⁺

Example 121 Preparation of4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid

Ethyl4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}-benzoate(32 mg, 0.06 mmol) prepared in Example 120 was treated in a similarmanner to Example 8 to give4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid (8 mg, 28%) as a white solid.

APCI-MS: m/z 506/508 [M+H]⁺

Example 122 Preparation of 4-{[[(3-chloro-1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)-amino]sulfonyl}benzoic acid

-   (1) To a solution of ethyl    4-{[[(3-chloro-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate    (81 mg, 0.15 mmol) prepared in Example 120 in N,N-dimethylformamide    (1 mL) was added sodium hydride (9 mg, 0.22 mmol) at 0° C., and the    mixture was stirred at the same temperature for 30 minutes. To the    reaction solution was added methyl iodide (29 μL, 0.46 mmol), and    the mixture was stirred at room temperature for 18 hours. To the    reaction solution was added water, and the mixture was extracted    with ethyl acetate twice. The organic layer was combined, washed    with saturated brine, dried over anhydrous sodium sulfate, and then    concentrated under reduced pressure. The resulting residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=9:1→2:1) to give a crude ethyl    4-{[[(3-chloro-1-methyl-1H-indol-6-yl)methyl]    (4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoate (53.0 mg) as a    colorless powder.-   (2) The crude product was treated in a similar manner to Example 8    to give    4-{[[(3-chloro-1-methyl-1H-indol-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic    acid (38 mg, 48%, yields for two steps) as a white solid.

APCI-MS: m/z 520/522 [M+H]⁺

Example 123 Preparation of 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzamide

To a solution of sodium4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(100 mg, 0.186 mmol) prepared in Example 2, ammonium chloride (50 mg,0.929 mmol) and N,N-diisopropylethylamine (162 μL, 0.929 mmol) inN,N-dimethylacetamide (1.8 mL) was added2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (85 mg, 0.223 mmol) at 0° C., and themixture was stirred at room temperature overnight. To the reactionsolution was added saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate three times. Theorganic layer was combined, washed with water twice, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (chloroform:methanol=100:0→91:9) to give4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzamide(26 mg, 27%) as a colorless powder.

APCI-MS: m/z 516 [M+H]⁺

Example 124 Preparation ofN-methoxy-4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzamide

To a suspension of sodium4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate(107.7 mg, 0.200 mmol) prepared in Example 2 in chloroform (1 mL) wasadded oxalyl dichloride (21 μL, 0.240 mmol), and the mixture was stirredat room temperature for 2 hours. Then, thereto was added additionaloxalyl dichloride (21 μL, 0.24 mmol), and the mixture was stirred atroom temperature for 1 hour. The reaction solution was concentratedunder reduced pressure. Then, the resulting residue was suspended inchloroform (1 mL), and added dropwise to a suspension ofO-methylhydroxylamine hydrochloride (50.1 mg, 0.600 mmol) andtriethylamine (139 μL, 1.00 mmol) in chloroform (1 mL), and the mixturewas stirred at room temperature for 1 hour. The resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=3:1→0:10) to giveN-methoxy-4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzamide(88.1 mg, 81%) as a white powder.

APCI-MS m/z:546 [M+H]⁺.

Example 125 Preparation of4-(1-hydroxy-1-methylethyl)-N-(4-methylisoquinolin-3-yl)-N-[4-(trifluoromethoxy)benzyl]benzenesulfonamide

To a solution of4-acetyl-N-(4-methylisoquinolin-3-yl)-N-[4-(trifluoromethoxy)benzyl]benzenesulfonamide(98 mg, 0.190 mmol) prepared in Example 152 in diethyl ether (2 mL) wasadded methylmagnesium bromide (tetrahydrofuran solution, 3 mol/L, 0.229mmol) at 0° C., and the mixture was stirred at room temperatureovernight. To the reaction solution was added 1 mol/L hydrochloric acid,and the mixture was extracted with ethyl acetate three times. Theorganic layer was combined, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=80:20→40:60) to give(1-hydroxy-1-methylethyl)-N-(4-methylisoquinolin-3-yl)-N-[4-(trifluoromethoxy)benzyl]benzenesulfonamide(83 mg, 82%) as a colorless powder.

APCI-MS m/z:531 [M+H]⁺.

Examples 126 to 158

The corresponding starting compounds were treated in a similar manner toExamples 1, 2 and/or 8 to give the following compounds of Table 6.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 6 Example Structure Physical data 126

ESI-MS m/z: 482[M − Na]⁻ 127

APCI-MS m/z: 474[M + H]⁺ 128

APCI-MS m/z: 599[M + H]⁺ 129

APCI-MS m/z: 595/597[M + H]⁺ 130

APCI-MS m/z: 537/539[M + H]⁺ 131

APCI-MS m/z: 531[M + H]⁺ 132

APCI-MS m/z: 559[M + H]⁺ 133

APCI-MS m/z: 551/553[M + H]⁺ 134

APCI-MS m/z: 551/553[M + H]⁺ 135

APCI-MS m/z: 531[M + H]⁺ 136

APCI-MS m/z: 531[M + H]⁺ 137

APCI-MS m/z: 531[M + H]⁺ 138

ESI-MS m/z: 549/551[M − Na]⁻ 139

APCI-MS m/z: 473[M + H]⁺ 140

ESI-MS m/z: 549/551[M − Na]⁻ 141

ESI-MS m/z: 529[M − Na]⁻ 142

ESI-MS m/z: 515[M − Na]⁻ 143

APCI-MS m/z: 581/583[M + H]⁺ 144

APCI-MS m/z: 531[M + H]⁺ 145

APCI-MS m/z: 535[M + H]⁺ 146

APCI-MS m/z: 535[M + H]⁺ 147

ESI-MS m/z: 518[M − Na]⁻ 148

APCI-MS m/z: 615/617/619[M + H]⁺ 149

APCI-MS m/z: 533[M + H]⁺ 150

APCI-MS m/z: 587[M + H]⁺ 151

APCI-MS m/z: 528[M + H]⁺ 152

APCI-MS m/z: 515[M + H]⁺ 153

APCI-MS m/z: 609/611[M + H]⁺ 154

APCI-MS m/z: 581/583[M + H]⁺ 155

APCI-MS m/z: 531[M + H]⁺ 156

APCI-MS m/z: 503[M + H]⁺ 157

ESI-MS m/z: 516[M − Na]⁻ 158

ESI-MS m/z: 516[M − Na]−

Examples 159 to 210

The corresponding starting compounds were treated in a similar manner toExamples 3, 4 and/or 8 to give the following compounds of Table 7.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 7 Example Structure Physical data 159

ESI-MS m/z: 484[M − Na]⁻ 160

ESI-MS m/z: 498[M − Na]⁻ 161

ESI-MS m/z: 532/534[M − Na]⁻ 162

ESI-MS m/z: 532/534[M − Na]⁻ 163

ESI-MS m/z: 482[M − Na]⁻ 164

ESI-MS m/z: 487[M − Na]⁻ 165

ESI-MS m/z: 518/520[M − Na]⁻ 166

ESI-MS m/z: 518/520[M − Na]⁻ 167

ESI-MS m/z: 510[M − Na]⁻ 168

ESI-MS m/z: 544/546[M − Na]⁻ 169

APCI-MS m/z: 563[M + H]⁺ 170

APCI-MS m/z: 505[M + H]⁺ 171

APCI-MS m/z: 505[M + H]⁺ 172

APCI-MS m/z: 579[M + H]⁺ 173

APCI-MS m/z: 557[M + H]⁺ 174

APCI-MS m/z: 595[M + H]⁺ 175

APCI-MS m/z: 491[M + H]⁺ 176

APCI-MS m/z: 507/509[M + H]⁺ 177

APCI-MS m/z: 571[M + H]⁺ 178

APCI-MS m/z: 473[M + H]⁺ 179

APCI-MS m/z: 543[M + H]⁺ 180

APCI-MS m/z: 487[M + H]⁺ 181

APCI-MS m/z: 597/599[M + H]⁺ 182

APCI-MS m/z: 523[M + H]⁺ 183

APCI-MS m/z: 487[M + H]⁺ 184

ESI-MS m/z: 549[M − Na]⁻ 185

ESI-MS m/z: 581/583[M − Na]⁻ 186

APCI-MS m/z: 569[M + H]⁺ 187

APCI-MS m/z: 569[M + H]⁺ 188

APCI-MS m/z: 504[M + H]⁺ 189

APCI-MS m/z: 537[M + H]⁺ 190

APCI-MS m/z: 504[M + H]⁺ 191

APCI-MS m/z: 523[M + H]⁺ 192

APCI-MS m/z: 531[M + H]⁺ 193

APCI-MS m/z: 555[M + H]⁺ 194

APCI-MS m/z: 525[M + H]⁺ 195

APCI-MS m/z: 525[M + H]⁺ 196

APCI-MS m/z: 523/525[M + H]⁺ 197

APCI-MS m/z: 523/525[M + H]⁺ 198

APCI-MS m/z: 523/525[M + H]⁺ 199

APCI-MS m/z: 523/525[M + H]⁺ 200

APCI-MS m/z: 523/525[M + H]⁺ 201

APCI-MS m/z: 557/559[M + H]⁺ 202

APCI-MS m/z: 557/559[M + H]⁺ 203

APCI-MS m/z: 541[M + H]⁺ 204

APCI-MS m/z: 541[M + H]⁺ 205

APCI-MS m/z: 523[M + H]⁺ 206

APCI-MS m/z: 523[M + H]⁺ 207

APCI-MS m/z: 541[M + H]⁺ 208

APCI-MS m/z: 541[M + H]⁺ 209

APCI-MS m/z: 537[M + H]⁺ 210

ESI-MS m/z: 565[M − Na]−

Examples 211 to 212

The corresponding starting compounds were treated in a similar manner toExamples 5, 6 and/or 8 to give the following compounds of Table 8.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 8 Example Structure Physical data 211

APCI-MS m/z: 540/542[M + H]⁺ 212

APCI-MS m/z: 543/545[M + H]⁺

Examples 213 to 218

The corresponding starting compounds were treated in a similar manner toExamples 8, 9 and/or 10 to give the following compounds of Table 9.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 9 Example Structure Physical data 213

APCI-MS m/z: 594[M + H]⁺ 214

APCI-MS m/z: 545[M + H]⁺ 215

APCI-MS m/z: 571[M + H]⁺ 216

APCI-MS m/z: 543[M + H]⁺ 217

APCI-MS m/z: 543[M + H]⁺ 218

APCI-MS m/z: 561[M + H]⁺

Examples 219 to 224

The corresponding starting compounds were treated in a similar manner toExamples 8, 13 and/or 14 to give the following compounds of Table 10.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 10 Example Structure Physical data 219

APCI-MS m/z: 577[M + H]⁺ 220

APCI-MS m/z: 591[M + H]⁺ 221

ESI-MS m/z: 611[M − Na]⁻ 222

APCI-MS m/z: 593/595[M + H]⁺ 223

APCI-MS m/z: 571[M + H]⁺ 224

APCI-MS m/z: 609[M + H]⁺

Examples 225 to 227

The corresponding starting compounds were treated in a similar manner toExample 97 to give the following compounds of Table 11. Interconversionsof a carboxylic acid compound and a salt thereof to each other may becarried out by a conventional salt formation and a conventionaldesalination, respectively.

TABLE 11 Ex- am- Physical ple Structure data 225

APCI-MS m/z: 559 [M + H]⁺ 226

APCI-MS m/z: 585 [M + H]⁺ 227

APCI-MS m/z: 545 [M + H]⁺

Examples 228 to 229

The corresponding starting compounds were treated in a similar manner toExample 100 to give the following compounds of Table 12.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 12 Example Structure Physical data 228

APCI-MS m/z: 561[M + H]⁺ 229

APCI-MS m/z: 561[M + H]⁺

Examples 230

The corresponding starting compound was treated in a similar manner toExamples 101 and 102 to give the following compound of Table 13.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 13 Example Structure Physical data 230

APCI-MS m/z: 551/553[M + H]⁺

Examples 231 to 232

The corresponding starting compounds were treated in a similar manner toExamples 103 and 104 to give the following compounds of Table 14.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 14 Ex- am- Physical ple Structure data 231

APCI-MS m/z: 585 [M + H]⁺ 232

APCI-MS m/z: 583 [M + H]⁺

Examples 233 to 235

The corresponding starting compounds were treated in a similar manner toExamples 105 and 106 to give the following compounds of Table 15.Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 15 Example Structure Physical data 233

ESI-MS m/z: 609/611[M − Na]⁻ 234

ESI-MS m/z: 577[M − Na]⁻ 235

APCI-MS m/z: 595[M − Na + 2H]⁺

Examples 236 to 237

The corresponding starting compounds were treated in a similar manner toExamples 120, 121 and/or 122 to give the following compounds of Table16. Interconversions of a carboxylic acid compound and a salt thereof toeach other may be carried out by a conventional salt formation and aconventional desalination, respectively.

TABLE 16 Example Structure Physical data 236

APCI-MS m/z: 506/508[M + H]⁺ 237

APCI-MS m/z: 520/522[M + H]⁺

Examples 238 to 240

The corresponding starting compounds were treated in a similar manner toExample 123 to give the following compounds of Table 17.

TABLE 17 Example Structure Physical data 238

APCI-MS m/z: 530[M + H]⁺ 239

APCI-MS m/z: 541[M + H]⁺ 240

APCI-MS m/z: 560[M + H]⁺

Examples 241 to 242

The corresponding starting compounds were treated in a similar manner toExample 124 to give the following compounds of Table 18.

TABLE 18 Example Structure Physical data 241

APCI-MS m/z: 542[M + H]⁺ 242

APCI-MS m/z: 570[M + H]⁺

Reference Example 1 Preparation of[3-fluoro-4-(trifluoromethoxy)phenyl]methanol

(1) To a solution of 3-fluoro-4-(trifluoromethoxy)benzoic acid (1.00 g,4.46 mmol) in ethanol (10 ml) was added thionyl chloride (1.33 g, 11.2mmol) at 0° C. The reaction solution was slowly warmed to roomtemperature, and stirred at the same temperature overnight. The reactionsolution was poured into saturated aqueous sodium bicarbonate solution,and extracted with ethyl acetate twice. The organic layer was combined,washed with saturated brine, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=10:0→9:1) to give ethyl 3-fluoro-4-(trifluoromethoxy)benzoate(0.72 g, 64%) as a colorless and clear oil.

¹H-NMR (DMSO-d₆) δ 1.33 (3H, t, J=7.1 Hz), 4.35 (21-1, q, J=7.1 Hz),7.77-7.73 (1H, m), 7.92-7.90 (1H, m), 8.00 (1H, dd, J=10.6, 1.9 Hz).

(2) To a solution of the above compound (698 mg, 2.77 mmol) intetrahydrofuran (7 ml) was added lithium aluminum hydride (79 mg, 2.08mmol) at 0° C. The mixture was stirred at the same temperature for 30minutes, and stirred at room temperature for 5 hours. The reactionsolution was cooled to 0° C., and then thereto were added diethyl etherand 1 mol/L aqueous sodium hydroxide solution (10 ml). The mixture wasstirred at the same temperature for 15 minutes. The reaction solutionwas extracted with diethyl ether twice. The organic layer was combined,washed with saturated brine, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=6:1→2:1) to give the title compound,[3-fluoro-4-(trifluoromethoxy)phenyl]methanol (0.52 g, 90%) as acolorless and clear oil.

¹H-NMR (DMSO-d₆) δ 4.53 (2H, d, J=5.4 Hz), 5.44 (1H, t, J=5.7 Hz), 7.26(1H, m), 7.40 (1H, dd, J=11.5, 1.5 Hz), 7.53-7.49 (1H, m).

Reference Example 2 Preparation of4,7-dichloro-1-methyl-1H-pyrrolo[2,3-c]pyridine

(1) To a solution of 2,5-dichloro-3-nitropyridine (5.00 g, 25.9 mmol) intetrahydrofuran (164 ml) was added a solution of 1 mol/L vinylmagnesiumbromide in tetrahydrofuran (82.9 ml, 82.9 mmol) at −78° C. The mixturewas stirred at −20° C. overnight, and then to the reaction solution wasadded saturated aqueous ammonium chloride solution. The mixture wasextracted with ethyl acetate twice. The organic layer was combined,washed with water and saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=19:1→7:3), and then washed with diisopropyl ether to give4,7-dichloro-1H-pyrrolo[2,3-c]pyridine (1.12 g, 23%) as a pale yellowpowder.

APCI-MS m/z: 187/189[M+H]⁺.

(2) To a solution of the above compound (150 mg, 802 μmol) in dimethylsulfoxide (4.01 ml) were added potassium carbonate (228 mg, 1.60 mmol)and iodomethane (100 μl, 1.60 mmol) at room temperature. The mixture wasstirred at the same temperature overnight, and then to the reactionsolution was added water. The mixture was extracted with ethyl acetatetwice. The organic layer was combined, washed with water and saturatedbrine, filtered through a diatomite column, and then concentrated underreduced pressure to give the title compound,4,7-dichloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (156 mg, 97%) as ayellow solid.

APCI-MS m/z: 201/203[M+H]⁺.

Reference Example 3 Preparation of6-(bromomethyl)-3-fluoro-2-iodopyridine

(1) To a solution of 2-bromo-3-fluoro-6-methylpyridine (1000 mg, 5.26mmol) in 1,4-dioxane (16 mL) were added sodium iodide (1580 mg, 10.52mmol), copper (I) iodide (150 mg, 0.26 mmol),N,N′-dimethylethylenediamine (62 μL, 0.58 mmol) under argon atmosphere.The reaction solution was heated to reflux for 4 hours, cooled to roomtemperature, and then to the reaction solution was added water. Themixture was extracted with ethyl acetate twice. The organic layer wascombined, washed with aqueous citric acid solution and saturated brine,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure to give 3-fluoro-2-iodo-6-methylpyridine (1169 mg, 94%) as awhite powder.

APCI-MS m/z: 238 [M+H]⁺.

(2) To a solution of the above compound (100 mg, 0.42 mmol) in1,2-dichloroethane (2 mL) were added N-bromosuccinimide (86 mg, 0.49mmol) and 2,2′-azobisisobutyronitrile (3 mg, 0.015 mmol), and themixture was stirred at 75° C. overnight. The mixture was cooled to roomtemperature, and then to the reaction solution was added saturatedaqueous sodium bicarbonate solution. The mixture was extracted withethyl acetate twice. The organic layer was combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=97:3→9:1) togive the title compound, 6-(bromomethyl)-3-fluoro-2-iodopyridine. Theresulting compound was used in the next step without furtherpurification.

Reference Example 4 Preparation of 4-(2-methoxyethoxy)benzyl4-methylbenzenesulfonate

(1) To a solution of 4-(2-methoxyethoxy)benzoic acid (100 mg, 0.51 mmol)in N,N-dimethylformamide (2 mL) were added potassium carbonate (282 mg,2.04 mmol) and iodomethane (79 μL, 1.27 mmol) at room temperature. Themixture was stirred at the same temperature overnight, and then to thereaction solution was added water. The mixture was extracted with ethylacetate twice. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was dissolvedin tetrahydrofuran (3 mL), and then thereto was added lithiumborohydride (53 mg, 2.45 mmol) at 0° C. The reaction solution was slowlywarmed to room temperature, and stirred for 3 days. To the reactionsolution was added water, and the mixture was extracted with ethylacetate twice. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give[4-(2-methoxyethoxy)phenyl]methanol (61 mg, 68%) as a colorless andclear oil.

APCI-MS m/z: 200[M+NH₄]⁺.

(2) To a solution of the above compound (58 mg, 0.32 mmol) indichloromethane (1.5 mL) were added p-toluenesulfonyl chloride (79 mg,0.41 mmol), N,N-diisopropylethylamine (162 μL, 0.95 mmol), andN,N-dimethyl-4-aminopyridine (8 mg, 0.064 mmol) at 0° C. The reactionsolution was slowly warmed to room temperature, and stirred for 7 hours.To the reaction solution was added water, and the mixture was extractedwith ethyl acetate twice. The organic layer was combined, washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give the title compound,4-(2-methoxyethoxy)benzyl 4-methylbenzenesulfonate. The resultingcompound was used in the next step without further purification.

Reference Example 5 Preparation of[4-fluoro-5-(trifluoromethyl)-2-thienyl]methanol

(1) To a solution of N,N-diisopropylamine (680 μL, 5.19 mmol) intetrahydrofuran (5 ml) was added dropwise a solution of 1.67 mol/Ln-butyllithium in hexane (3.11 ml, 5.19 mmol) at −78° C. under argonatmosphere, and the mixture was stirred at the same temperature for 15minutes. The reaction solution was slowly warmed to 0° C., and stirredfor 20 minutes, and then cooled to −40° C. Then, thereto was addeddropwise a solution of 3-bromo-2-(trifluoromethyl)thiophene (1000 mg,4.33 mmol) in tetrahydrofuran (15 ml). The mixture was stirred at thesame temperature for 20 minutes, and the reaction solution was slowlywarmed to −10° C., and then stirred for 5 minutes. The reaction solutionwas cooled to −40° C., and then thereto was added dropwiseN,N-dimethylformamide (1 mL). Then, the mixture was slowly warmed to 0°C., and stirred overnight. To the reaction solution was added water, andthe mixture was extracted with ethyl acetate twice. The organic layerwas combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:0→9:1) to give4-bromo-5-(trifluoromethyl)thiophene-2-carbaldehyde (527 mg, 47%) as ayellow oil.

¹H-NMR (CDCl₃) δ 7.71 (1H, m), 9.93 (1H, s).

(2) To a solution of the above compound (520 mg, 2.01 mmol) in ethanol(10 mL) was added sodium borohydride (152 mg, 4.02 mmol) at 0° C. Themixture was stirred at the same temperature for 1 hour, and then to thereaction solution was added water. The mixture was extracted with ethylacetate twice. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give[4-bromo-5-(trifluoromethyl)-2-thienyl]methanol (432 mg, 82%) as a paleyellow oil.

¹H-NMR (CDCl₃) δ 2.01 (1H, t, J=6.0 Hz), 4.84 (2H, d, J=6.0 Hz), 6.96(1H, s).

(3) To a solution of the above compound (427 mg, 1.64 mmol) indichloromethane (6 mL) were added chloromethyl methyl ether (311 μL,4.09 mmol) and N,N-diisopropylethylamine (1289 μL, 7.38 mmol) at roomtemperature. The mixture was stirred at the same temperature for 3 days,and then to the reaction solution was added water. The mixture wasextracted with ethyl acetate twice. The organic layer was combined,washed with water and saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:0→9:1) to give3-bromo-5-[(methoxymethoxy)methyl]-2-(trifluoromethyl)thiophene (363 mg,73%) as a colorless and clear oil.

¹H-NMR (CDCl₃) δ 3.41 (3H, s), 4.70 (2H, s), 4.72 (2H, s), 6.97 (1H, s).

(4) To a solution of the above compound (358 mg, 1.17 mmol) intetrahydrofuran (4 mL) was added dropwise a solution of 1.67 mol/Ln-butyllithium in hexane (0.84 ml, 1.41 mmol) at −78° C. under argonatmosphere. The mixture was stirred at the same temperature for 90minutes, and then thereto was added a solution of N-fluorobenzenesulfonimide (553 mg, 1.76 mmol) in tetrahydrofuran (6 mL). The reactionsolution was slowly warmed to room temperature, and stirred overnight.To the reaction solution was added water, and the mixture was extractedwith ethyl acetate twice. The organic layer was combined, washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:0→19:1) togive an about 1:1 mixture of3-fluoro-5-[(methoxymethoxy)methyl]-2-(trifluoromethyl)thiophene and2-[(methoxymethoxy)methyl]-5-(trifluoromethyl)thiophene. The resultingmixture was dissolved in ethanol (2 mL), and then thereto was added 6mol/L hydrochloric acid solution (1 mL) at room temperature. The mixturewas stirred at the same temperature overnight, and then the reactionsolution was alkalified by the addition of saturated aqueous sodiumhydrogen carbonate solution, and then extracted with ethyl acetatetwice. The organic layer was combined, washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=4:1→3:2) to give the titlecompound, [4-fluoro-5-(trifluoromethyl)-2-thienyl]methanol (34 mg, 15%)as a colorless and clear oil.

¹H-NMR (CDCl₃) δ 2.01 (1H, t, J=6.0 Hz), 4.81 (2H, d, J=6.0 Hz), 6.76(1H, s).

Reference Example 6 Preparation of [4-(cyclopropoxy)phenyl]methanol

(1) To a solution of 1-bromo-4-(cyclopropoxy)benzene (492 mg, 2.31 mmol)in tetrahydrofuran (10 ml) was added dropwise a solution of 2.66 mol/Ln-butyllithium in hexane (0.955 ml, 2.54 mmol) at −78° C. under argonatmosphere, and the mixture was stirred for 2.5 hours. Then, thereto wasadded dropwise N,N-dimethylformamide (0.358 ml, 4.62 mmol) at the sametemperature, and the mixture was stirred for 3.5 hours with slowlywarming to room temperature. To the reaction solution was addedsaturated aqueous ammonium chloride solution, and the mixture wasstirred, and then extracted with ethyl acetate three times. The organiclayer was combined, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give a crude4-(cyclopropoxy)benzaldehyde as a pale yellow liquid. The resultingcompound was used in the next step without further purification.(2) A solution of the above crude product in methanol (5 ml) was cooledto 0° C., and then thereto was added sodium borohydride (175 mg, 4.62mmol), and the mixture was stirred for 1 hour. Then, thereto was addedsaturated brine, and then the reaction solution was concentrated underreduced pressure. The resulting residue was dissolved in ethyl acetate,washed with saturated brine, and the organic layer was dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1→3:2) to give the titlecompound, [4-(cyclopropoxy)phenyl]methanol (216 mg, 57%, yields for 2steps) as a white solid.

APCI-MS m/z: 182 [M+NH₄]⁺.

Reference Example 7 Preparation of [4-(cyclopropylmethyl)phenyl]methanol

1-Bromo-4-(cyclopropylmethyl)benzene was treated in a similar manner tothe methods of Reference examples 6-(1) and (2) to give the titlecompound.

APCI-MS m/z: 180[M+NH₄]⁺.

Reference Example 8 Preparation of(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)methanol

1,1-Dimethylindane-5-carbaldehyde prepared in the method ofWO2006/013048A1 was treated in a similar manner to the method ofReference example 6-(2) to give the title compound.

APCI-MS m/z: 194[M+NH₄]⁺.

Reference Example 9 Preparation of(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)methanol

To a solution of methyl3,3-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylate (44 mg, 0.21 mmol)prepared in the method of US2009/105209 in tetrahydrofuran (1.5 mL) wereadded lithium borohydride (23 mg, 1.07 mmol) and methanol (43 μL, 1.07mmol) at 0° C., and the mixture was stirred at room temperature for 1hour. To the reaction solution was added water, and the mixture wasextracted with ethyl acetate twice. The organic layer was combined,washed with water and saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure to give the titlecompound (38 mg, 100%) as a colorless and clear oil.

APCI-MS m/z: 196 [M+NH₄]⁺.

Reference Example 10 Preparation of(1,1-dimethyl-1,3-dihydro-2-benzofuran-5-yl)methanol

5-Bromo-1,1-dimethyl-1,3-dihydro-2-benzofuran prepared in the method ofUS2010/197591A1 was treated in a similar manner to the methods ofReference examples 6-(1) and (2) to give the title compound.

APCI-MS m/z: 196[M+NH₄]⁺.

Reference Example 11 Preparation of(2,2-dimethyl-2,3-dihydro-1H-inden-5-yl)methanol

2,2-Dimethylindane-5-carbaldehyde prepared in the method of U.S. Pat.No. 4,952,722 was treated in a similar manner to the method of Referenceexample 6-(2) to give the title compound.

APCI-MS m/z: 194[M+NH₄]⁺.

Reference Example 12 Preparation of 4-chloro-3-methylquinolin-2-amine

(1) A solution of 2,4-dichloro-3-methylquinoline (1.08 g, 5.1 mmol),tris(dibenzylideneacetone)dipalladium (12 mg, 0.0025 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (32 mg, 0.01 mmol) andsodium-t-butoxide (735 mg, 7.6 mmol) in toluene (51 mL) was stirred atroom temperature for 5 minutes. To the solution was added benzophenoneimine (852 μL, 5.1 mmol), and the mixture was stirred at 100° C. for 4hours. The reaction solution was cooled to room temperature, and thenthereto was added diethyl ether (10 mL). The mixture was stirred for 10minutes. The solution was filtered through diatomaceous earth, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane→hexane:ethyl acetate=10:1)to give a crude 4-chloro-N-(diphenylmethylene)-3-methylquinolin-2-amine(910 mg, 50%) as a yellow solid.(2) The above crude compound (910 mg, 2.6 mmol) was dissolved intetrahydrofuran (10 mL), and then thereto was added 1 mol/L hydrochloricacid solution (2 mL), and the mixture was stirred at room temperaturefor 1 hour. Then, thereto was added additional 1 mol/L hydrochloric acidsolution (1 mL), and then the mixture was stirred for 30 minutes. To thesolution was added saturated aqueous sodium bicarbonate solution, andthe mixture was extracted with ethyl acetate twice. The organic layerwas combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1→1:1) to give 4-chloro-3-methylquinolin-2-amine(261 mg, 53%) as a white solid.

APCI-MS m/z: 193/195 [M+H]⁺.

Reference Example 13 Preparation of1,7-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-amine

(1) To a solution of 6-chloro-7-iodo-1H-pyrrolo[3,2-c]pyridine (600 mg,2.15 mmol) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride(130 mg, 3.25 mmol) under argon atmosphere, and the mixture was stirredat room temperature for 1 hour. The reaction solution was cooled to 0°C., and then thereto was added dropwise dimethyl sulfate (250 μL, 2.64mmol). Then, the mixture was stirred at room temperature for 3 hours. Tothe reaction solution was added water, and then the mixture wasextracted with ethyl acetate three times. The organic layer wascombined, washed with water and saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=97:3→75:25) to give6-chloro-7-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (540 mg, 86%) as acolorless powder.

APCI-MS m/z: 293/295[M+H]⁺.

(2) To a solution of the above compound (650 mg, 2.22 mmol) intetrahydrofuran (13 mL) was added dropwise a solution of 1.65 mol/Ln-butyllithium in hexane (1.75 mL, 2.89 mmol) at −78° C. under argonatmosphere. The mixture was stirred at the same temperature for 2 hours,and then thereto was added dropwise a solution of iodomethane (180 μL,2.89 mmol) in tetrahydrofuran (4 mL), and the mixture was stirred at thesame temperature for 1 hour. The reaction solution was slowly warmed to10° C., and then to the reaction solution was added water, and themixture was extracted with ethyl acetate three times. The organic layerwas combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=95:5→65:35) to give6-chloro-1,7-dimethyl-1H-pyrrolo[3,2-c]pyridine (204 mg, 51%) as acolorless powder.

APCI-MS m/z: 181/183 [M+H]⁺.

(3) A suspension of the above compound (200 mg, 1.11 mmol), benzophenoneimine (560 μL, 3.35 mmol), tris(dibenzylideneacetone)dipalladium (100mg, 0.11 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (140 mg,0.22 mmol) and sodium-t-butoxide (320 mg, 3.33 mmol) in toluene (10 mL)was stirred at 110° C. for 15 hours under microwave irradiation. Aftercooling, to the reaction solution was added water, and the mixture wasextracted with ethyl acetate three times. The organic layer wascombined, washed with water and saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=98:2→40:60) to giveN-(diphenylmethylene)-1,7-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-amine (244mg, 68%) as a yellow powder.

APCI-MS m/z: 326[M+H]⁺.

(4) To a solution of the above compound (240 mg, 0.74 mmol) intetrahydrofuran (10 mL) was added 1 mol/L hydrochloric acid solution(3.70 mL, 3.70 mmol), and the mixture was stirred at room temperaturefor 2 hours. The reaction solution was alkalified by the addition ofsaturated aqueous sodium hydrogen carbonate solution, and then theretowas added sodium chloride, and the mixture was extracted with ethylacetate six times. The organic layer was combined, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(NH-silica gel, chloroform:methanol=100:0→95:5) to give1,7-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-amine (106 mg, 90%) as a paleyellow powder.

APCI-MS m/z: 162[M+H]⁺.

Reference Example 14 Preparation of 4-methoxyisoquinolin-3-amine

(1) To a solution of 4-methoxyisoquinoline (130 mg, 0.82 mmol) in 98%sulfuric acid (0.61 mL) was added potassium nitrate (91 mg, 0.90 mmol),and the mixture was heated to 60° C. and stirred for 2 hours. Thereaction solution was cooled, and then thereto was added ice. Thepowders were filtered to dissolve in ethyl acetate. The solution waswashed with aqueous sodium hydrogen carbonate solution and saturatedbrine, and then dried over anhydrous sodium sulfate, followed byconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=9:1→2:8) togive 4-methoxy-3-nitroisoquinoline (58.3 mg, 35%) as a pale yellowpowder.

APCI-MS m/z: 205[M+H]⁺.

(2) To a mixed solution of the above compound (67.0 mg, 0.33 mmol) inacetic acid (3.3 mL) and ethanol (3.3 mL) was added reduced iron (183.0mg, 3.28 mmol), and the mixture was heated to reflux under argonatmosphere for 2 hours. The reaction solution was cooled, and thendiluted with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate solution. Then, the insoluble was filtered off. Thefiltrate was washed with saturated brine, and then dried over anhydroussodium sulfate, followed by concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1→1:3) to give 4-methoxyisoquinolin-3-amine(48.1 mg, 84%) as a white powder.

APCI-MS m/z: 175[M+H]⁺.

Reference Example 15 Preparation of 5-chloro-3-methylquinolin-2-amine

(1) A solution of diethyl(1-cyanoethyl)phosphonic acid ester (1.26 g,8.5 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C., and thenthereto was added potassium-t-butoxide (744 mg, 8.5 mmol). The mixturewas stirred at the same temperature for 10 minutes. Then, thereto wasadded 2-chloro-6-nitrobenzaldehyde (948 mg, 6.6 mmol), and then themixture was stirred at 60° C. for 5 hours. The reaction solution wascooled to room temperature, and then to the reaction solution was addedsaturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate twice. The organic layer was combined,washed with water and saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography(hexane→hexane:ethyl acetate=3:1) to give3-(2-chloro-6-nitrophenyl)-2-methylacrylonitrile (0.98 g, 86%) as ayellow oil.

APCI-MS m/z: 240/242[M+NE₄]⁺

(2) To a solution of the above compound (2.0 g, 9 mmol) in ethanol (180mL) was added tin (II) chloride dihydrate (12.2 g, 54 mmol) at roomtemperature, and the mixture was heated to reflux for 45 minutes. Thesolution was cooled to room temperature, and then thereto was addedsaturated aqueous hydrochloric acid solution (15 mL), and the mixturewas heated to reflux for 6 hours. The solution was cooled to roomtemperature, and slowly added dropwise to saturated aqueous sodiumbicarbonate solution. The suspension was filtered through diatomaceousearth, and the resulting solution was extracted with chloroform twice.The organic layer was combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. To a solution of the resulting residue in ethanol (50 mL) wasadded sodium ethoxide (535 mg, 13.5 mmol) at room temperature, and thenthe mixture was heated to reflux for 4 hours. Then, thereto was addedsodium ethoxide (357 mg, 9 mmol), and then the mixture was heated toreflux for 17 hours. The reaction solution was cooled to roomtemperature, and then to the reaction solution was added water, and themixture was extracted with ethyl acetate twice. The organic layer wascombined, washed with water and saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1→1:1) to give 5-chloro-3-methylquinolin-2-amine(457 mg, 26%) as a pale brown solid.

APCI-MS m/z: 193/195 [M+H]⁺.

Reference Example 16 Preparation of 4,5-dimethylisoquinolin-3-amine

(1) A solution of sodium ethoxide (8.76 mL, 23.5 mmol, 21 wt % ethanolsolution) in ethanol (10 mL) was cooled to 0° C. under argon atmosphere,and thereto was added dropwise a solution of3-bromo-2-(cyanomethyl)benzonitrile (4.33 g, 19.6 mmol) and iodomethane(1.46 mL, 23.5 mmol) in tetrahydrofuran (10 mL) over 30 minutes, andthen the mixture was stirred at room temperature for 6.5 hours. Themixture was concentrated under reduced pressure, and then the residuewas neutralized by 2 mol/L hydrochloric acid, and extracted with ethylacetate three times. The organic layer was combined, washed withsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate/hexane=10%→40%) togive 3-bromo-2-(1-cyanoethyl)benzonitrile (3.11 g, 67%) as a yellowviscous material.

APCI-MS: m/z 252/254 [M+NH_(4]) ⁺

(2) The above compound (3.11 g, 13.2 mmol), trimethylboroxine (1.85 mL,13.2 mmol), tetrakis(triphenylphosphine)palladium (0) (306 mg, 0.265mmol) and potassium carbonate (5.49 g, 39.7 mmol) were stirred inN,N-dimethylformamide (10 mL) at 120° C. for 6 hours under argonatmosphere. The mixture was cooled to room temperature, and then theretowas added water, and the mixture was stirred and extracted with ethylacetate three times. The organic layer was combined, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(ethyl acetate/hexane=10%→40%) to give2-(1-cyanoethyl)-3-methylbenzonitrile (1.99 g, 89%) as a brown solid.

APCI-MS: m/z 188 [M+NH₄]⁺

(3) A suspension of the above compound (1.99 g, 11.7 mmol) in aceticacid (1 mL) was cooled to 0° C., and then thereto was added hydrogenbromide (5 mL, 25% acetic acid solution), and the mixture was stirredfor 2 hours with warming to room temperature. The mixture was dilutedwith diisopropyl ether, and the generated solid was filtered. To theresulting solid was added saturated aqueous sodium hydrogen carbonatesolution, and the mixture was stirred and the solid was filtered anddried to give a crude product. The product was suspended to wash withdiisopropyl ether, and the solid was filtered, and then dried to give1-bromo-4,5-dimethylisoquinolin-3-amine (843 mg, 29%) as a yellowpowder.

APCI-MS: m/z 251/253 [M+11]⁺

(4) To a solution of the above compound (843 mg, 3.36 mmol) inmethanol-tetrahydrofuran (1:1, 10 mL) were added 10% palladium-carbon(42.2 mg) and triethylamine (0.561 mL, 4.03 mmol), and the mixture wasstirred at room temperature for 2 hours under hydrogen atmosphere. Themixture was filtered through diatomaceous earth by ethyl acetate, andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate, and washed with saturated aqueous sodiumhydrogen carbonate solution. The organic layer was dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate/hexane=25%→50%) to give 4,5-dimethylisoquinolin-3-amine(456 mg, 79%) as a yellow powder.

APCI-MS: m/z 173 [M+H]⁺

Reference Example 17 Preparation of 4,6-dimethylisoquinolin-3-amine

4-Bromo-2-(cyanomethyl)benzonitrile was treated in a similar manner toReference examples 16-(1) to (4) to give 4,6-dimethylisoquinolin-3-amineas a pale yellow solid.

APCI-MS: m/z 173 [M+H]⁺

Reference Example 18 Preparation of 4,6-dimethylisoquinolin-3-amine

2-(cyanomethyl)-5-methylbenzonitrile was treated in a similar manner toReference examples 16-(1), (3) and (4) to give4,7-dimethylisoquinolin-3-amine as a yellow powder.

APCI-MS: m/z 173 [M+H]⁺

Reference Example 19 Preparation of 4,8-dimethylisoquinolin-3-amine

2-(Cyanomethyl)-6-methylbenzonitrile was treated in a similar manner toReference examples 16-(1), (3) and (4) to give4,8-dimethylisoquinolin-3-amine as a yellow powder.

APCI-MS: m/z 173 [M+H]⁺

Reference Example 20 Preparation of1-bromo-5-chloro-4-methylisoquinolin-3-amine

3-Chloro-2-(cyanomethyl)benzonitrile was treated in a similar manner toReference examples 16-(1) and (3) to give1-bromo-5-chloro-4-methylisoquinolin-3-amine.

APCI-MS: m/z 271/273 [M+H]⁺

Reference Example 21 Preparation of 1-bromo-5-chloroisoquinolin-3-amine

3-Chloro-2-(cyanomethyl)benzonitrile (883 g, 5 mmol) was treated in asimilar manner to Reference example 16-(3) to give1-bromo-5-chloroisoquinolin-3-amine (717 mg, 56%) as a yellow powder.

APCI-MS: m/z 257/259 [M+H]⁺

Reference Example 22 Preparation of 5-methyl-1,7-naphthyridin-6-amine

(1) To a solution of 3-(cyanomethyl)pyridine-2-carbonitrile (synthesizedby the method of Synthesis 1973, 47, 530 mg, 3.70 mmol) intetrahydrofuran (14 mL) was added dropwise a solution of 1.65 mol/Ln-butyllithium in hexane (2.60 mL, 4.29 mmol) at −78° C. under argonatmosphere. The mixture was stirred at the same temperature for 30minutes, and then thereto was added dropwise iodomethane (300 μL, 4.81mmol) in tetrahydrofuran (7 mL). The mixture was stirred at the sametemperature for 1 hour. The reaction solution was slowly warmed to roomtemperature, and then to the reaction solution was added water, and themixture was extracted with ethyl acetate four times. The organic layerwas combined, washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=95:5→50:50) to give 3-(1-cyanoethyl)pyridine-2-carbonitrile (514mg, 88%) as a yellow oil.

APCI-MS m/z: 175[M+NH₄]⁺.

(2) The above compound was treated in a similar manner to Referenceexamples 16-(3) and (4) to give 5-methyl-1,7-naphthyridin-6-amine.

APCI-MS m/z: 160 [M+H]⁺.

Reference Example 23 Preparation of4,7-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridine

(1) To a solution of phosphorus oxychloride (6.40 μL, 73.21 mmol) inchloroform (61.2 mL) was added 2,5-dichloro-4-nitropyridine 1-oxide(3.06 g, 14.64 mmol), and the mixture was stirred under refluxovernight. The reaction solution was poured into ice, adjusted bysaturated aqueous sodium hydrogen carbonate solution to pH7 to 8, andextracted with chloroform three times. The organic layer was combined,filtered through Phase-separator (Varian Inc.), and then concentratedunder reduced pressure to give a crude 2,5-dichloro-4-nitropyridine(2.98 g, quant.) as a yellow oil.(2) To a solution of vinylmagnesium bromide (54.04 mmol) intetrahydrofuran (104 mL) was added a solution of the above crudecompound (2.98 g, 15.44 mmol) in tetrahydrofuran (100 mL) at 0° C. over40 minutes, and the mixture was stirred at room temperature for 1 hour.To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, filtered throughPhase-separator (Varian Inc.), and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=80:20→50:50) to give4,7-dichloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 27%) as a pale yellowpowder.

APCI-MS m/z: 187/189[M+H]⁺.

(3) To a solution of the above compound (300 mg, 1.60 mmol) inN,N-dimethylformamide (3 mL) were added potassium carbonate (443 mg,3.21 mmol) and iodomethane (150 μL, 2.41 mmol), and the mixture wasstirred at room temperature overnight. To the reaction solution wasadded water, and the mixture was extracted with ethyl acetate threetimes. Then, the organic layer was combined, and washed with watertwice. The organic layer was filtered through Phase-separator (VarianInc.), and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=100:0→70:30) to give4,7-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridine (240 mg, 75%) as acolorless powder.

APCI-MS m/z: 201/203 [M+H]⁺.

Reference Example 24 Preparation of4-bromo-1-isopropylisoquinolin-3-amine

(1) 1-Bromoisoquinoline-3-amine and isopropenylboronic acid pinacolester were treated in a similar manner to Examples 97-(1) and (2) togive 1-isopropylisoquinolin-3-amine as a white powder.

APCI-MS m/z: 187 [M+H]⁺.

(2) A solution of the above compound (186.0 mg, 1.00 mmol) andN-bromosuccinimide (214.0 mg, 1.20 mmol) in methanol was stirred at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:0→3:1) to give4-bromo-1-isopropylisoquinolin-3-amine (155.1 mg, 58%) as a whitepowder.

APCI-MS m/z: 265/267[M+H]⁺

Reference Example 25 Preparation of4-iodo-1-isopropylisoquinolin-3-amine

(1) 1-Bromoisoquinoline-3-amine and isopropenylboronic acid pinacolester were treated in a similar manner to Examples 97-(1) and (2) togive 1-isopropylisoquinolin-3-amine as a white powder.

APCI-MS m/z: 187 [M+H]⁺.

(2) To a solution of the above compound (146.0 mg, 0.784 mmol) inethanol were added iodine (219.0 mg, 0.862 mmol) and silver sulfate(269.0 mg, 0.862 mmol), and the mixture was stirred at room temperaturefor 4 hours. The reaction solution was diluted with ethyl acetate, andthe insoluble was filtered off and the filtrate was concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:0→17:3) to give4-iodo-1-isopropylisoquinolin-3-amine (78.7 mg, 32%) as a pale yellowpowder.

APCI-MS m/z: 313 [M+H]⁺.

Reference Example 26 Preparation of 1,4-diisopropylisoquinolin-3-amine

4-Bromo-1-isopropylisoquinolin-3-amine obtained in Reference example 24and isopropenylboronic acid pinacol ester were treated in a similarmanner to Examples 97-(1) and (2) to give1,4-diisopropylisoquinolin-3-amine as a white powder.

APCI-MS m/z: 229 [M+H]⁺.

Reference Example 27 Preparation of4-bromo-1-cyclopropylisoquinolin-3-amine

(1) 1-Bromoisoquinoline-3-amine was treated in a similar manner toExample 9-(2) to give 1-cyclopropylisoquinolin-3-amine as a whitepowder.

APCI-MS m/z: 185 [M+H]⁺

(2) The above compound was treated in a similar manner to Referenceexample 24-(2) to give 4-bromo-1-cyclopropylisoquinolin-3-amine as awhite powder.

APCI-MS m/z: 263/265 [M+H]⁺.

Reference Example 28 Preparation of 4-cyclopropylisoquinolin-3-amine

4-Bromoisoquinoline-3-amine was treated in a similar manner to Example103 to give 4-cyclopropylisoquinolin-3-amine as a pale yellow powder.

APCI-MS m/z: 185 [M+H]⁺.

Reference Example 29 Preparation of[4-(cyclopropylmethyl)-2-fluorophenyl]methanol

(1) Methyl 4-bromo-2-fluorobenzoate (424 mg, 1.82 mmol), allyl tributyltin (0.846 mL, 2.73 mmol), tetrakis(triphenylphosphine)palladium (0)(105 mg, 0.091 mmol) and cesium fluoride (415 mg, 2.73 mmol) were heatedto reflux in 1,4-dioxane (10 mL) for 7 hours under argon atmosphere. Themixture was cooled to room temperature, and then filtered throughdiatomaceous earth by ethyl acetate and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=2%→10%) to give methyl4-allyl-2-fluorobenzoate (333 mg, 94%) as a pale yellow viscousmaterial.

APCI-MS: m/z 195 [M+H]⁺

(2) To a solution of the above compound (333 mg, 1.71 mmol) in1,2-dichloroethane (10 mL) was added chloroiodomethane (1.25 mL, 17.1mmol) under argon atmosphere, and then thereto slowly added dropwisediethylzinc (8.57 mL, 8.57 mmol, hexane solution), and the mixture wasstirred for 16 hours at room temperature and for 7 hours at 50° C. Themixture was cooled to room temperature, and then thereto was addedsaturated ammonium chloride solution, and the mixture was extracted withchloroform three times. The organic layer was dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was stirred in the mixture of microcapsulated osmiumtetraoxide (219 mg, 0.0865 mmol), N-methylmorpholine-N-oxide (260 mg,2.22 mmol) and acetone-acetonitrile-water (1:1:1, 6 mL) at roomtemperature for 21 hours. The mixture was filtered and concentrated togive a crude product, and then the product was purified by silica gelcolumn chromatography (ethyl acetate/hexane=2%→15%) to give methyl4-(cyclopropylmethyl)-2-fluorobenzoate (155 mg, 44%) as a colorlessliquid.

APCI-MS: m/z 209 [M+H]⁺

(3) To a solution of the above compound (155 mg, 0.744 mmol) intetrahydrofuran (5 mL) were added lithium borohydride (81.1 mg, 3.72mmol) and methanol (0.151 mL, 3.72 mmol) at 0° C. under argonatmosphere, and the mixture was stirred at room temperature for 3 days.Then, thereto was added saturated brine, and the mixture was extractedwith ethyl acetate three times, followed by dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate/hexane=15%→40%) to give[4-(cyclopropylmethyl)-2-fluorophenyl]methanol (126 mg, 94%) as acolorless liquid.

APCI-MS: m/z 198 [M+NH₄]⁺

Reference Example 30 Preparation of[4-(cyclopropylmethyl)-3-fluorophenyl]methanol

Methyl 4-bromo-3-fluorobenzoate was treated in a similar manner toReference examples 29-(1) to (3) to give[4-(cyclopropylmethyl)-3-fluorophenyl]methanol as a colorless liquid.

APCI-MS: m/z 198 [M+NH₄]⁺

Reference Example 31 Preparation of(4-{[1-(trifluoromethyl)cyclopropyl]methyl}phenyl)methanol

(1) To a solution of 4-bromoiodobenzene (2150 mg, 7.60 mmol) intetrahydrofuran (20 mL) was added dropwise a solution of 1.67 mol/Ln-butyllithium in hexane (4.50 mL, 7.52 mmol) at −78° C. under argonatmosphere. The mixture was stirred at the same temperature for 1 hour,and then thereto was added dropwise a solution ofN-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide(synthesized by the method of Organic Process Research and Development2009, 13, 576, 1000 mg, 5.07 mmol) in tetrahydrofuran (10 mL), and themixture was stirred at the same temperature for 1 hour. To the reactionsolution was added saturated aqueous ammonium chloride solution at −78°C., and then the mixture was warmed to room temperature and extractedwith ethyl acetate three times. The organic layer was combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=100:0→95:5) to give(4-bromophenyl)[1-(trifluoromethyl)cyclopropyl]methanone (783 mg, 76%)as a pale brown oil.

¹H-NMR (CDCl₃) δ 1.36-1.50 (4H, m), 7.61 (2H, d, J=8.7 Hz), 7.79 (2H, d,J=8.7 Hz).

(2) To a solution of the above compound (780 mg, 3.26 mmol) in ethanol(10 mL) was added 78% hydrazine monohydrate (1000 μL, 16.1 mmol). Thereaction solution was heated to reflux overnight, and cooled to roomtemperature, and then to the reaction solution was added water, and themixture was extracted with ethyl acetate three times. The organic layerwas combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressureto give a crude (4-bromophenyl)[1-(trifluoromethyl)cyclopropyl]methanonehydrazone (784 mg) as a pale brown oil. The resultant was used in thenext step without further purification.

APCI-MS m/z: 307/309[M+Na₄]⁺

(3) To a solution of the above crude product (775 mg) in ethylene glycol(8 mL) was added potassium hydroxide (580 mg, 10.3 mmol), and themixture was heated to stir at 180° C. for 2 hours. The mixture wascooled to room temperature, and then to the reaction solution was addedwater, and the mixture was extracted with diethyl ether three times. Theorganic layer was combined, washed with 2 mol/L hydrochloric acidsolution, water and saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane) togive 1-bromo-4-{[1-(trifluoromethyl)cyclopropyl]methyl}benzene (148 mg,21%, yields for two steps) as a colorless oil.

¹H-NMR (CDCl₃) δ 0.48-0.53 (2H, m), 0.92-0.97 (2H, m), 2.95 (2H, s),7.04 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz).

(4) To a mixed solution of the above compound (145 mg, 0.52 mmol),palladium acetate (15 mg, 0.07 mmol),1,1′-bis(diphenylphosphino)ferrocene (75 mg, 0.14 mmol) inN,N-dimethylformamide (5 mL) and methanol (1.1 mL) was addedtriethylamine (200 μL, 1.43 mmol). The reaction solution was stirredunder carbon monoxide atmosphere at 90° C. overnight. The solution wascooled to room temperature, and then to the reaction solution was addedwater, and the mixture was extracted with ethyl acetate three times. Theorganic layer was combined, washed with water and saturated brine, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=98:2→90:10) to give methyl4-{[1-(trifluoromethyl)cyclopropyl]methyl}benzoate (129 mg, 96%) as acolorless oil.

APCI-MS m/z: 259[M+H]⁺.

(5) To a solution of the above compound (110 mg, 0.43 mmol) intetrahydrofuran (4 mL) and methanol (110 μL, 2.71 mmol) was addedlithium borohydride (60 mg, 2.75 mmol) at 0° C. The mixture was stirredat room temperature overnight, and then to the reaction solution wasadded water at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give a crude(4-{[1-(trifluoromethyl)cyclopropyl]methyl}phenyl)methanol (103 mg) as acolorless oil. The resultant was used in the next step without furtherpurification.

APCI-MS mz: 248[M+NH₄]⁺.

Reference Example 32 Preparation of{4-[cyclopropyl(difluoro)methyl]phenyl}methanol

(1) To a mixed solution of (4-bromophenyl)(cyclopropyl)methanone(synthesized by the method of Pesticide Science 1980, 11, 513, 5.00 g,22.0 mmol), palladium acetate (0.52 g, 2.3 mmol) and1,1′-bis(diphenylphosphino)ferrocene (2.50 g, 4.5 mmol) inN,N-dimethylformamide (150 mL) and methanol (40 mL) was addedtriethylamine (6.7 mL, 48.1 mmol). The reaction solution was stirredunder carbon monoxide atmosphere at 90° C. overnight. The solution wascooled to room temperature, and then to the reaction solution was addedwater, and the mixture was extracted with ethyl acetate three times. Theorganic layer was combined, washed with water and saturated brine, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=98:2→80:20) to give methyl4-(cyclopropylcarbonyl)benzoate (4.28 g, 94%) as a colorless powder.

APCI-MS m/z: 205[M+H]⁺.

(2) The above compound (1000 mg, 4.90 mmol) was dissolved inbis(2-methoxyethyl)aminosulfuric acid trifluoride (8.0 mL, 43.4 mmol) intest tubes made of fluororesin. Then, thereto was added dropwisemethanol (60 μL, 1.48 mmol) at 0° C., and then the mixture was heated tostir at 80° C. for 8 days. The reaction solution was cooled, and thenthereto was added dropwise saturated aqueous sodium hydrogen carbonatesolution at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=98:2→90:10) togive methyl 4-[cyclopropyl(difluoro)methyl]benzoate (924 mg, 84%) as apale yellow oil.

¹H-NMR (DMSO-d₆) δ 0.64-0.74 (4H, m), 1.66-1.79 (1H, m), 3.88 (3H, s),7.72 (2H, d, J=8.8 Hz), 8.07 (2H, d, J=8.8 Hz).

(3) To a solution of the above compound (920 mg, 4.07 mmol) intetrahydrofuran (25 mL) were added lithium borohydride (340 mg, 15.6mmol) and methanol (630 μL, 15.5 mmol) at 0° C. The mixture was stirredat room temperature overnight, and then to the reaction solution wasadded water at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=95:5→65:35) togive {4-[cyclopropyl(difluoro)methyl]phenyl}methanol (905 mg, 98%) as acolorless oil.

¹H-NMR (DMSO-d₆) δ 0.58-0.71 (4H, m), 1.61-1.75 (1H, m), 4.54 (2H, d,J=5.7 Hz), 5.29 (1H, t, J=5.7 Hz), 7.42 (2H, d, J=8.8 Hz), 7.50 (2H, d,J=8.5 Hz).

Reference Example 33 Preparation of{3-[cyclopropyl(difluoro)methyl]phenyl}methanol

Ethyl 3-(cyclopropylcarbonyl)benzoate (synthesized by the method ofWO2006/067445) was treated in a similar manner to Reference examples32-(2) and (3) to give {3-[cyclopropyl(difluoro)methyl]phenyl}methanol.

¹H-NMR (DMSO-d₆) δ 0.60-0.72 (4H, m), 1.61-1.75 (1H, m), 4.55 (2H, d,J=5.1 Hz), 5.32 (1H, t, J=5.4 Hz), 7.39-7.45 (3H, m), 7.50 (1H, s).

Reference Example 34 Preparation of{4-[difluoro(1-methylcyclopropyl)methyl]phenyl}methanol

(1) To a solution of methyl 4-(cyclopropylcarbonyl)benzoate (500 mg,2.45 mmol) in tetrahydrofuran (12 mL) was added dropwise a solution of 1mol/L lithium hexamethyldisilazane in tetrahydrofuran (3.0 mL, 3.00mmol) at −78° C. under argon atmosphere, and the mixture was stirred for15 minutes. To the mixture was added dropwise iodomethane (200 μL, 3.21mmol) at the same temperature, and the reaction solution was slowlywarmed to room temperature and stirred overnight. To the reactionsolution was added saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate three times. The organic layerwas combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0→97:3) to give methyl4-[(1-methylcyclopropyl)carbonyl]benzoate (45 mg, 8%) as a colorlessoil.

APCI-MS m/z: 219[M+H]⁺.

(2) Methyl 4-[(1-methylcyclopropyl)carbonyl]benzoate was treated in asimilar manner to Reference examples 32-(2) and (3) to give{4-[difluoro(1-methylcyclopropyl)methyl]phenyl}methanol.

APCI-MS m/z: 230[M+NH₄]⁺.

Reference Example 35 Preparation of{4-[cyclopropyl(difluoro)methyl]-3-fluorophenyl}methanol

(4-Bromo-2-fluorophenyl)cyclopropylketone was treated in a similarmanner to Reference examples 32-(1), (2) and (3) to give{4-[cyclopropyl(difluoro)methyl]-3-fluorophenyl}methanol.

¹H-NMR (DMSO-d₆) δ 0.60-0.74 (4H, m), 1.69-1.84 (1H, m), 4.55 (2H, d,J=4.2 Hz), 5.43 (1H, t, J=5.3 Hz), 7.23 (1H, s), 7.26 (1H, d, J=6.7 Hz),7.51 (1H, t, J=8.0 Hz).

Reference Example 36 Preparation of

(5-Bromo-2-fluorophenyl)(cyclopropyl)methanone (synthesized by themethod of Bioorganic & Medicinal Chemistry Letters 2010, 20, 1652) wastreated in a similar manner to

Reference examples 32-(1), (2) and (3) to give{3-[cyclopropyl(difluoro)methyl]-4-fluorophenyl}methanol.

¹H-NMR (DMSO-d₆) δ 0.61-0.74 (4H, m), 1.69-1.84 (1H, m), 4.51 (2H, d,J=4.8 Hz), 5.35 (1H, t, J=5.6 Hz), 7.29 (1H, dd, J=11.2, 8.5 Hz),7.45-7.52 (2H, m).

Reference Example 37 Preparation of{3-chloro-4-[cyclopropyl(difluoro)methyl]phenyl}methanol

(1) To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide(synthesized by the method of Bioorganic & Medicinal Chemistry Letters2003, 13, 3983, 5.90 g, 21.0 mmol) in tetrahydrofuran (180 mL) was addeddropwise a solution of 0.7 mol/L cyclopropylmagnesium bromide intetrahydrofuran (65.0 mL, 45.5 mmol) at 0° C. The mixture was stirred atthe same temperature for 4 hours, and then to the reaction solution wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate three times. The organic layer wascombined, washed with water and saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0→93:7) to give(4-bromo-2-chlorophenyl)(cyclopropyl)methanone (3.75 g, 68%) as a paleyellow oil.

APCI-MS m/z: 259/261/263 [M+H]⁺.

(2) (4-Bromo-2-chlorophenyl)(cyclopropyl)methanone was treated in asimilar manner to Reference examples 32-(1), (2) and (3) to give{3-chloro-4-[cyclopropyl(difluoro)methyl]phenyl}methanol.

¹H-NMR (DMSO-d₆) δ 0.62-0.74 (4H, m), 1.84-1.98 (1H, m), 4.54 (2H, d,J=4.5 Hz), 5.42 (1H, t, J=5.4 Hz), 7.37 (1H, d, J=8.1 Hz), 7.50 (1H, s),7.58 (1H, d, J=7.9 Hz).

Reference Example 38 Preparation of{4-[cyclobutyl(difluoro)methyl]phenyl}methanol

To a solution of ethyl 4-[cyclobutyl(difluoro)methyl]benzoate(synthesized by the method of WO2005/032465, 140 mg, 0.55 mmol) intetrahydrofuran (5 mL) and methanol (112 μL, 2.76 mmol) was addedlithium borohydride (60 mg, 2.75 mmol) at 0° C. The mixture was stirredat room temperature for 3 hours, and then to the reaction solution wasadded water at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give a crude{4-[cyclobutyl(difluoro)methyl]phenyl}methanol (111 mg) as a colorlessoil. The resultant was used in the next step without furtherpurification.

APCI-MS m/z: 230[M+NH₄]⁺.

Reference Example 39 Preparation of1-cyclopropyl-2,2,2-trifluoro-1-[4-(hydroxymethyl)phenyl]ethanol

(1) To a solution of (4-bromophenyl)(cyclopropyl)methanone (587 mg, 2.60mmol) in tetrahydrofuran (5.2 mL) were added molecular sieves 4 Å (500mg), trimethylsilyl trifluoromethane (772 μL, 5.20 mmol) andtetrabutylammonium fluoride (tetrahydrofuran solution, 1 mol/L, 3.9 mL,3.90 mmol) at 0° C., and the mixture was stirred at room temperature for18 hours. The solution was filtered through diatomaceous earth, and thenthereto was added 1 mol/L hydrochloric acid solution (10 mL), and themixture was extracted with ethyl acetate twice. The organic layer wascombined, washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=20:1→5:1) to give1-(4-bromophenyl)-1-cyclopropyl-2,2,2-trifluoroethanol (747 mg, 97%) asa colorless oil.

APCI-MS m/z: 353/355[M+CH₃COO]⁻.

(2) The above compound (747 mg, 2.53 mmol) was treated in a similarmanner to Reference examples 6-(1) and (2) to give1-cyclopropyl-2,2,2-trifluoro-1-[4-(hydroxymethyl)phenyl]ethanol (112mg, 18%) as a colorless oil.

ESI-MS m/z: 353/355[M−H]⁻.

Reference Example 40 Preparation of{4-[(trifluoromethoxy)methyl]phenyl}methanol

(1) To a solution of 4-[(trifluoromethoxy)methyl]benzoic acid (500 mg,2.27 mmol) in N,N-dimethylformamide (25 mL) were added iodomethane (300μL, 4.82 mmol) and potassium carbonate (1000 mg, 7.24 mmol). The mixturewas stirred at room temperature overnight, and then to the reactionsolution was added water, and the mixture was extracted with ethylacetate three times. The organic layer was combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=99:1→80:20) togive methyl 4-[(trifluoromethoxy)methyl]benzoate (453 mg, 85%) as a palebrown oil.

APCI-MS m/z: 235[M+H]⁺.

(2) To a solution of the above compound (450 mg, 1.92 mmol) intetrahydrofuran (5 mL) and methanol (130 μL, 3.20 mmol) was addedlithium borohydride (70 mg, 3.20 mmol) at 0° C. The mixture was stirredat room temperature overnight, and then to the reaction solution wasadded water at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=85:15) to give{4-[(trifluoromethoxy)methyl]phenyl}methanol (239 mg, 60%) as acolorless solid.

APCI-MS m/z: 224 [M+NH₄]⁺.

Reference Example 41 Preparation of1,1,1-trifluoro-2-[2-fluoro-4-(hydroxymethyl)phenyl]propan-2-ol

(1) To a mixed solution of 1-(4-bromo-2-fluorophenyl)ethanone (1.00 g,4.5 mmol), palladium acetate (0.12 g, 0.54 mmol) and1,1′-bis(diphenylphosphino)ferrocene (0.50 g, 0.90 mmol) inN,N-dimethylacetamide (22 mL) and methanol (7 mL) was addedtriethylamine (1.3 mL, 9.2 mmol). The reaction solution was stirredunder carbon monoxide atmosphere at 90° C. overnight. The solution wascooled to room temperature, and then the reaction solution was filteredthrough diatomaceous earth and silica gel, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=100:0→60:40) to give methyl4-acetyl-3-fluorobenzoate (0.83 g, 93%) as a pale yellow powder.

APCI-MS m/z: 194[M+H]⁺.

(2) To a solution of the above compound (825 mg, 4.21 mmol) intetrahydrofuran (8.4 mL) were added trimethylsilyl trifluoromethane(1240 μL, 8.41 mmol) and tetrabutylammonium fluoride (tetrahydrofuransolution, 1 mol/L, 6.3 mL, 6.31 mmol) at 0° C., and the mixture wasstirred at room temperature for 3 hours. To the solution was added 1mol/L hydrochloric acid solution, and the mixture was extracted withethyl acetate three times. The organic layer was combined, filteredthrough Phase-separator (Varian Inc.), and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=100:0→60:40) to give methyl3-fluoro-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzoate (650 mg,58%) as a pale yellow oil.

ESI-MS m/z: 324[M−H]⁻.

(3) To a solution of the above compound (648 mg, 2.43 mmol) intetrahydrofuran (4 mL) was added lithium aluminum hydride (110 mg, 2.92mmol) at 0° C. The mixture was stirred at room temperature for 5 hours,and then to the reaction solution were added water and 2N aqueous sodiumhydroxide solution at 0° C., and the mixture was filtered throughdiatomaceous earth. The filtrate was extracted with ethyl acetate threetimes. The organic layer was combined, filtered through Phase-separator(Varian Inc.), and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=80:20→40:60) to give1,1,1-trifluoro-2-[2-fluoro-4-(hydroxymethyl)phenyl]propan-2-ol (494 mg,85%) as a colorless powder.

APCI-MS m/z: 256[M+NH₄]⁺.

Reference Example 42 Preparation of2-[2-chloro-4-(hydroxymethyl)phenyl]-1,1,1-trifluoropropan-2-ol

(1) To a solution of 4-acetyl-3-chlorobenzoic acid (synthesized by themethod of Tetrahedron 1988, 44, 1631, 700 mg, 3.52 mmol) inN,N-dimethylformamide (4 mL) were added potassium carbonate (974 mg,7.05 mmol) and iodomethane (658 μL, 10.57 mmol) at room temperature, andthe mixture was stirred at room temperature for 1 hour. To the reactionsolution was added water, and the mixture was extracted with ethylacetate three times. The organic layer was combined, filtered throughPhase-separator (Varian Inc.), and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=100:0→75:25) to give methyl4-acetyl-3-chlorobenzoate (707 mg, 94%) as a pale yellow powder.

APCI-MS m/z: 213/215 [M+H]⁺.

(2) Methyl 4-acetyl-3-chlorobenzoate was treated in a similar manner toReference examples 41-(2) and (3) to give2-[2-chloro-4-(hydroxymethyl)phenyl]-1,1,1-trifluoropropan-2-ol.

APCI-MS m/z: 272/274[M+NH₄]⁺.

Reference Example 43 Preparation of3,3,4,4,4-pentafluoro-2-[4-(hydroxymethyl)phenyl]butan-2-ol

(1) To a solution of methyl 4-acetylbenzoate (700 mg, 3.85 mmol) intetrahydrofuran (7.7 mL) were added (pentafluoroethyl)trimethylsilane(1370 mg, 6.93 mmol) and tetrabutylammonium fluoride (tetrahydrofuransolution, 1 mol/L, 5.7 μL, 5.78 mmol) at 0° C., and the mixture wasstirred at room temperature overnight. To the solution was added 1 mol/Lhydrochloric acid solution, and the mixture was extracted with ethylacetate three times. The organic layer was combined, filtered throughPhase-separator (Varian Inc.), and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=100:0→70:30) to give methyl4-(2,2,3,3,3-pentafluoro-1-hydroxy-1-methylpropyl)benzoate (765 mg, 67%)as a pale yellow viscous material.

APCI-MS m/z: 316[M+NH₄]⁺.

(2) To a solution of the above compound (760 mg, 2.55 mmol) intetrahydrofuran (13 mL) were added lithium borohydride (278 mg, 12.7mmol) and methanol (6516 μL, 12.7 mmol) at 0° C. The mixture was stirredat room temperature overnight, and then to the reaction solution wasadded water at 0° C., and the mixture was extracted with ethyl acetatethree times. The organic layer was combined, filtered throughPhase-separator (Varian Inc.), and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=100:0→60:40) to give3,3,4,4,4-pentafluoro-2-[4-(hydroxymethyl)phenyl]butan-2-ol (580 mg,84%) as a colorless powder.

APCI-MS m/z: 288[M+NH₄]⁺.

Reference Example 44 Preparation of(7-fluoro-2,3-dihydro-1H-inden-5-yl)methanol

(1) To a solution of 6-bromo-4-fluoroindan-1-one (57 mg, 0.26 mmol) intrifluoroacetic acid (1.1 mL) was added triethylsilane (103 μL, 0.65mmol), and the mixture was stirred at room temperature overnight. Thereaction solution was poured into ice water, and the mixture wasextracted with ethyl acetate three times. The organic layer wascombined, washed with saturated aqueous sodium hydrogen carbonatesolution, and the organic layer was filtered through Phase-separator(Varian Inc.), and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0) to give a crude 6-bromo-4-fluoroindane (61mg) as a yellow oil. The resultant was used in the next step withoutfurther purification.(2) The above crude product was treated in a similar manner to Referenceexample 41-(1) to give a crude methyl 7-fluoroindane-5-carboxylate. Theresultant was used in the next step without further purification.(3) The above crude product was treated in a similar manner to Referenceexample 43-(2) to give a crude(7-fluoro-2,3-dihydro-1H-inden-5-yl)methanol. The resultant was used inthe next step without further purification.

Reference Example 45 Preparation of5-(hydroxymethyl)-1-(trifluoromethyl)indan-1-ol

5-Bromoindan-1-one was treated in a similar manner to Reference examples41-(1), (2) and (3) to give5-(hydroxymethyl)-1-(trifluoromethyl)indan-1-ol.

APCI-MS m/z: 250[M+NH₄]⁺.

Reference Example 46 Preparation of[5-(cyclopropylmethyl)pyrimidin-2-yl]methanol

(1) To a solution of 2-(methylthio)pyridine-5-carbaldehyde (2000 mg,12.97 mmol) in tetrahydrofuran (20 mL) was added a solution of 0.5 mol/Lcyclopropylmagnesium bromide in tetrahydrofuran (28.6 mL) at −40° C.under argon atmosphere. The reaction solution was stirred at the sametemperature for 10 minutes, and then slowly warmed to 0° C. and stirredfor 1 hour. To the reaction solution was added aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=70:30→60:70) to givecyclopropyl[2-(methylthio)pyrimidin-5-yl]methanol (822 mg, 32%) as acolorless oil.

APCI-MS m/z: 197[M+H]⁺

(2) To a solution of the above compound (815 mg, 4.15 mmol) inchloroform (12 mL) was added triethylsilane (1.99 mL, 12.46 mmol) atroom temperature. To the reaction solution was added dropwisetrifluoroacetic acid (1.54 mL, 20.15 mmol) under ice cooling, and thenthe mixture was slowly warmed to room temperature and stirred for 4days. To the reaction solution was added saturated aqueous sodiumbicarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=95:5→75:25) to give5-(cyclopropylmethyl)-2-(methylthio)pyrimidine (229 mg, 31%) as acolorless oil.

APCI-MS m/z: 181[M+H]⁺

(3) To a solution of the above compound (225 mg, 1.25 mmol) indichloromethane (5 mL) was added dropwise a solution ofmetachloroperoxybenzoic acid (624 mg, 2.50 mmol) in dichloromethane (5mL) at 0° C. The reaction solution was slowly warmed to room temperatureand stirred for 1 hour and 30 minutes, and then thereto was addedaqueous sodium thiosulfate solution, and the mixture was stirred foradditional 30 minutes. To the reaction solution was added saturatedaqueous sodium bicarbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=70:30→65:65) to give5-(cyclopropylmethyl)-2-(methylsulfonyl)pyrimidine (173 mg, 65%) as acolorless oil.

APCI-MS m/z: 213[M+H]⁺

(4) To a solution of the above compound (169 mg, 0.796 mmol) indichloromethane (4 mL) was added tetrabutylammonium cyanide (235 mg,0.876 mmol) at room temperature, and the mixture was stirred at the sametemperature overnight. To the reaction solution was addedtetrabutylammonium cyanide (85 mg), and the mixture was stirred foradditional 3 hours, and then thereto was added saturated aqueous sodiumbicarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=95:5→80:20) to give a crude5-(cyclopropylmethyl)pyrimidine-2-carbonitrile (130 mg) as a colorlessoil. The resultant was used in the next step without furtherpurification.

APCI-MS m/z: 160[M+H]⁺

(5) To a solution of the crude product (125 mg) in tetrahydrofuran (3mL) was added a solution of 1.0 mol/L diisobutylaluminum hydride intoluene (0.82 mL) at −78° C. under argon atmosphere. The mixture wasstirred at the same temperature for 2 hours, and then to the reactionsolution was added methanol, and the mixture was slowly warmed to roomtemperature. To the reaction solution was added 6.0 mol/L hydrochloricacid solution, and the mixture was stirred at room temperature for 2hours, and then thereto was added saturated aqueous sodium bicarbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=65:35→35:65) to give a crude5-(cyclopropylmethyl)pyrimidine-2-carbaldehyde (94 mg) as a colorlessoil. The resultant was used in the next step without furtherpurification.

APCI-MS m/z: 163[M+H]⁺

(6) To a mixed solution of the above crude product (88 mg) in ethanol (1mL) and tetrahydrofuran (1 mL) was added sodium borohydride (24 mg,0.643 mmol) at 0° C. The mixture was stirred at the same temperature for30 minutes, and then to the reaction solution was added aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=50:50→0:100) to give[5-(cyclopropylmethyl)pyrimidin-2-yl]methanol (24 mg) as a colorlessoil.

APCI-MS m/z: 165 [M+H]⁺

Reference Example 47 Preparation of(5-chloro-1-ethyl-1H-indol-2-yl)methanol

(1) A mixture of ethyl 5-chloro-1H-indole-2-carboxylate (500 mg, 2.17mmol), potassium carbonate (450 mg, 3.25 mmol), iodoethane (260 μL, 3.25mmol) and N,N-dimethylformamide (10.8 mL) was stirred at roomtemperature for 3 days. To the reaction solution was added water, andthe mixture was extracted with ethyl acetate twice. The organic layerwas combined, washed with water three times, and the organic layer wasfiltered through diatomaceous earth, followed by silica gel, and thenthe filtrate was concentrated under reduced pressure to give ethyl5-chloro-1-ethyl-1H-indole-2-carboxylate (566 mg, 100%) as an oil.

APCI-MS m/z: 252/254[M+H]⁺.

(2) To a solution of the above compound (561 mg, 2.23 mmol) in diethylether (11.1 mL) was added lithium aluminum hydride (127 mg, 3.34 mmol)in divided portions at 0° C., and the mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture were sequentiallyadded water (127 μL), 15% aqueous sodium hydroxide solution (127 μL) andwater (381 μL), and then the mixture was filtered through diatomaceousearth. The filtrate was concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=9:1→3:2) to give the title compound(5-chloro-1-ethyl-1H-indol-2-yl)methanol (429 mg, 92%) as a powder.

APCI-MS mz: 210/212[M+H]⁺.

Reference Example 48 Preparation of(6-chloro-1-ethyl-1H-indol-2-yl)methanol

Ethyl 6-chloro-1H-indole-2-carboxylate was treated in a similar mannerto Reference examples 47-(1) and (2) to give the title compound(6-chloro-1-ethyl-1H-indol-2-yl)methanol.

APCI-MS m/z: 210/212[M+H]⁺.

Reference Example 49 Preparation of(4-chloro-1-methyl-1H-indol-2-yl)methanol

4-Chloro-1H-indole-2-carboxylic acid and iodomethane were treated in asimilar manner to Reference examples 47-(1) and (2) to give the titlecompound (4-chloro-1-methyl-1H-indol-2-yl)methanol.

APCI-MS m/z: 196/198[M+H]⁺.

Reference Example 50 Preparation of(1-cyclopropyl-1H-indol-2-yl)methanol

(1) A mixture of methyl 1H-indole-2-carboxylate (1.00 g, 5.71 mmol),cyclopropylboronic acid (981 mg, 11.4 mmol), copper (II) acetate (1.04g, 5.71 mmol), 2,2-bipyridyl (892 mg, 5.71 mmol), sodium carbonate (1.21g, 11.4 mmol) and 1,2-dichloroethane (15.0 mL) was stirred at 70° C. for19 hours. Then, thereto were added cyclopropylboronic acid (981 mg, 11.4mmol) and sodium carbonate (1.21 g, 11.4 mmol), and the mixture wasstirred at 70° C. for 8 hours, and then thereto were addedcyclopropylboronic acid (981 mg, 11.4 mmol), sodium carbonate (1.21 g,11.4 mmol), copper (II) acetate (1.04 g, 5.71 mmol) and 2,2-bipyridyl(892 mg, 5.71 mmol), and the mixture was stirred at 70° C. for 16 hours.The mixture was let stand to cool, and then to the reaction mixture wasadded saturated aqueous ammonium chloride solution. The mixture wasfiltered through diatomaceous earth, and the filtrate was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over sodium sulfate, and then the filtrate was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=19:1→17:3) to give ethyl1-cyclopropyl-1H-indole-2-carboxylate (882 mg, 72%) as a powder.

APCI-MS m/z: 216[M+H]⁺.

(2) To a solution of the above compound (865 mg, 4.02 mmol) in toluene(20.1 mL) was added a solution of 1.01 mol/L diisobutylaluminum hydridein toluene (9.94 mL, 10.0 mmol) at −78° C., and the mixture was stirredat −78° C. for 1.5 hours. To the reaction mixture was added methanol,and the mixture was acidified by the addition of 1 mol/L hydrochloricacid, and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over sodium sulfate, and then thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane:ethylacetate=9:1→17:3) to give (1-cyclopropyl-1H-indol-2-yl)methanol (708 mg,94%) as a powder.

APCI-MS m/z: 188[M+H]⁺.

Reference Example 51 Preparation of(5-chloro-1-cyclopropyl-1H-indol-2-yl)methanol

Ethyl 5-chloro-1H-indole-2-carboxylate was treated in a similar mannerto Reference examples 50-(1) and (2) to give the title compound(5-chloro-1-cyclopropyl-1H-indol-2-yl)methanol.

APCI-MS m/z: 222/224[M+H]⁺.

Reference Example 52 Preparation of(1-methyl-2,3-dihydro-1H-indol-6-yl)methanol

To a solution of 1-methylindoline-6-carboxylic acid (321 mg, 1.80 mmol)in tetrahydrofuran (6 mL) was added N,N′-carbodiimidazole (309 mg, 1.89mmol) at room temperature. The mixture was stirred at 50° C. for 15minutes, and then cooled to 0° C. Then, thereto were added water (1 mL)and sodium hydroborate (204 mg, 5.40 mmol), and the mixture was stirredat the same temperature for 1 hour. The reaction solution was cooled toroom temperature, and then thereto was added water, and the mixture wasextracted with ethyl acetate twice. The organic layer was combined,washed with saturated brine, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=5:1→1:1) to give (1-methyl-2,3-dihydro-1H-indol-6-yl)methanol(245 mg, 83%) as a pale yellow oil.

APCI-MS m/z: 164[M+H]⁺.

Reference Example 53 Preparation of tert-butyl3-chloro-6-(hydroxymethyl)-1H-indazole-1-carboxylate

(1) A solution of methyl 3-chloro-1H-indazole-6-carboxylate (891 mg, 4.2mmol) in tetrahydrofuran (10 mL) was cooled to −78° C., and then theretowas added dropwise diisobutylaluminum hydride (tetrahydrofuran solution,1 mol/L, 12.7 mL, 12.6 mmol) at the same temperature, and the mixturewas stirred at the same temperature for 2 hours. To the reactionsolution was added water, and the mixture was extracted with ethylacetate twice. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography hexane→hexane:ethyl acetate=2:1) togive (3-chloro-1H-indazol-6-yl)methanol (344 mg, 45%) as a yellow solid.

APCI-MS m/z: 183/185[M+H]⁺.

(2) To a solution of the above compound (270 mg, 1.50 mmol) indichloromethane (15 mL) was added di-t-butyl dicarbonate (323 mg, 1.50mmol) at room temperature, and the mixture was stirred at the sametemperature for 18 hours. To the reaction solution was addedN,N-dimethyl-4-aminopyridine (5 mg, catalytic amounts), and the mixturewas stirred for 1 hour. The reaction solution was concentrated underreduced pressure, and purified by silica gel column chromatography(hexane→hexane:ethyl acetate=2:1) to give tert-butyl3-chloro-6-(hydroxymethyl)-1H-indazole-1-carboxylate (356 mg, 85%) as apale yellow oil.

APCI-MS m/z: 283/285[M+H]⁺.

Reference Example 54 Preparation of(4,6-difluoro-1-benzothien-2-yl)methanol

(1) To a suspension of 2,4,6-trifluorobenzaldehyde (5.00 g, 31.2 mmol)and potassium carbonate (5.61 g, 40.6 mmol) in N,N-dimethylformamide (63mL) was added ethyl thioglycolate (3.40 g, 28.3 mmol) at 0° C. Themixture was stirred at room temperature overnight, and then heated tostir at 60° C. for 6 hours. The mixture was cooled to room temperature,and then to the reaction solution was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=97:3→93:7) togive ethyl 4,6-difluoro-1-benzothiophene-2-carboxylate (1.95 g, 29%) asa pale yellow solid.

APCI-MS m/z: 243[M+H]⁺.

(2) To a solution of the above compound (1000 mg, 4.13 mmol) in diethylether (21 mL) was added lithium aluminum hydride (235 mg, 6.19 mmol) individed portions at 0° C. under argon atmosphere, and the mixture wasstirred at room temperature for 40 minutes. To the reaction solutionwere added water (0.24 mL) and 15% aqueous sodium hydroxide solution(0.24 mL) under ice cooling, and then thereto was added additional water(0.72 mL), and then the mixture was stirred at room temperature. Theinsoluble was filtered off, washed with diethyl ether, and then thefiltrate was combined with the washing, and concentrated under reducedpressure. The resulting residue was washed with hexane-diisopropyl etherto give (4,6-difluoro-1-benzothien-2-yl)methanol (731 mg, 88%) as acolorless powder.

¹H-NMR (DMSO-d₆) δ 4.74 (2H, d, J=5.7 Hz), 5.75 (1H, t, J=5.9 Hz), 7.26(1H, dt, J=10.1, 2.1 Hz), 7.30 (1H, s), 7.77 (1H, dd, J=8.8, 2.1 Hz).

Reference Example 55 Preparation of(5,7-difluoro-1-benzothien-2-yl)methanol

(1) To a solution of 5,7-difluoro-1-benzothiophene-2-carboxylic acid(synthesized by the method of WO2003/055878, 1.95 g, 9.10 mmol),N,O-dimethylhydroxyamine hydrochloride (977 mg, 10.0 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g,10.0 mmol) and N-hydroxybenzotriazole (1.35 g, 10.0 mmol) indichloromethane (20 mL) was added triethylamine (1.90 mL, 13.7 mmol) atroom temperature. The mixture was stirred at room temperature overnight,and then to the reaction solution was added 10% hydrochloric acidsolution, and the mixture was extracted with chloroform. The organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution, dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure to give a crude5,7-difluoro-N-methoxy-N-methyl-1-benzothiophene-2-carboxamide (2.48 g)as a colorless solid. The resultant was used in the next step withoutfurther purification.

APCI-MS m/z: 258[M+H]⁺.

(2) To a solution of the crude product (2.45 g) in tetrahydrofuran (40mL) was added dropwise a solution of 1 mol/L diisobutylaluminum hydridein toluene (14.3 mL, 14.3 mmol) at −70° C. under argon atmosphere. Thereaction solution was slowly warmed to −40° C., and then to the reactionsolution was added 10% hydrochloric acid solution (50 mL), and themixture was extracted with diethyl ether. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure to give5,7-difluoro-1-benzothiophene-2-carbaldehyde (1.67 g, 92%, yields fortwo steps) as a colorless solid.

APCI-MS m/z: 213 [M+H+MeOH—H₂O]⁺.

(3) To a solution of the above compound (1000 mg, 5.05 mmol) in methanol(25 mL) was added sodium borohydride (383 mg, 10.1 mmol) at 0° C. Themixture was stirred at room temperature for 40 minutes, and then to thereaction solution was added water, and the mixture was extracted withethyl acetate twice. The organic layer was combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=90:10→70:30)to give (5,7-difluoro-1-benzothien-2-yl)methanol (933 mg, 92%) as acolorless solid.

¹H-NMR (DMSO-d₆) δ 4.77 (2H, dd, J=5.7, 0.9 Hz), 5.84 (1H, t, J=5.7 Hz),7.28 (1H, dt, J=9.9, 2.3 Hz), 7.35 (1H, d, J=3.6 Hz), 7.54 (1H, dd,J=9.4, 2.1 Hz).

Reference Example 56 Preparation of (7-chloro-1-benzothien-2-yl)methanol

To a solution of 7-chloro-1-benzothiophene-2-carboxylic acid(synthesized by the method of Journal of Chemical Society Perkin Trans.1, 1984, 385, 1.00 g, 4.70 mmol) in tetrahydrofuran (17 mL) was added asolution of 0.95 mol/L borane-tetrahydrofuran complex in tetrahydrofuran(9.90 mL, 9.41 mmol) at 0° C. The mixture was stirred at roomtemperature overnight, and then to the reaction solution was addedwater, and the mixture was concentrated under reduced pressure to removesolvent. To the resulting residue was added saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate twice. The organic layer was combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was washedwith hexane-diisopropyl ether to give(7-chloro-1-benzothien-2-yl)methanol (842 mg, 90%) as a colorlesspowder.

APCI-MS m/z: 216/218 [M+NH₄]⁺.

Reference Example 57 Preparation of 5-(trifluoromethoxy)indan-1-ol

(2S)-1-(1,3,2-Dioxaborolan-2-yloxy)-3-methyl-1,1-diphenylbutan-2-amine(33 mg, 0.1 mmol) obtained in a similar manner to the method of EuropeanJournal of Organic Chemistry, 1999, p. 1775 (Eur. J. Org. Chem. 1999,1775) was suspended in tetrahydrofuran (5 mL), and then thereto wasadded borane dimethylsulfide complex (10 mol/L, 0.1 mL, 1 mmol) at roomtemperature. The mixture was stirred at the same temperature for 20minutes, and then thereto was added in divided portions5-trifluoromethoxyindan-1-one (0.217 g, 1 mmol) obtained in a similarmanner to the method of U.S. Pat. No. 6,159,996 over 1 hour, and themixture was stirred at room temperature overnight. The mixture wascooled to 5° C., and then thereto was added methanol (2 mL). The mixturewas stirred at the same temperature for 1 hour, and then the reactionsolution was concentrated, and then thereto was added chloroform. Thechloroform solution was poured into saturated aqueous ammonium chloridesolution, and extracted with chloroform three times, and the organiclayer was washed with saturated brine. The resultant was dried overmagnesium sulfate, and then concentrated. To the resulting residue wereadded diethyl ether and hexane, and the generated white solid wasfiltered off. The filtrate was concentrated to give a crude5-(trifluoromethoxy)indan-1-ol (62.5 mg). The resultant was used in thenext step without further purification.

Pharmacological Experiment

1. TRPM8 Inhibition Assay

Test Compound:

The compounds of Examples were used in TRPM8 inhibition assay.

Method:

The functional activity of compounds was determined by measuring changesin intracellular calcium concentration using a Ca²⁺ sensitivefluorescent dye. The changes in fluorescent signal were monitored by thecell imaging technology by Hamamatsu Photonics's Functional DrugScreening System (FDSS). Increases in intracellular Ca²⁺ concentrationwere readily detected upon activation with menthol.

HEK293 cells stably expressing human TRPM8 were grown in flasks. Onassay day, the culture medium was removed, and cells were washed withphosphate-buffered saline (PBS) and harvested with PBS containing 2 mMethylenediaminetetraacetic acid, disodium salt (EDTA, 2Na). The cellswere then incubated with assay buffer containing 3 μM Fura-2AM and 0.01%Pluronic F-127 for 60 min. Subsequently, suspended 20,000 to 50,000cells per well were incubated with test compound (at varyingconcentrations) in each well for 20 min at 37° C. Changes inintracellular Ca²⁺ evoked by 100 μM menthol were measured for 2 minusing FDSS. IC₅₀ vales were determined from four-pointconcentration-response studies. Curves were generated using the averageof quadruplicate wells for each data point.

Results:

The following Table 19 shows an IC₅₀ value of each test compound.

TABLE 19 Test Compound TRPM8 Blocking Test (Example No.) (IC₅₀, nM) 22.7 4 3.6 6 22 8 26 10 1.9 12 43 14 4.7 17 5.0 20 12 22 93 23 1.8 24 4.627 26 28 16 30 4.9 31 65 32 8.6 34 2.5 35 3.1 41 12 42 30 43 37 44 91 4535 46 17 51 26 52 20 56 4.7 60 8.1 61 1.3 62 8.3 64 11 66 38 67 67 70 9577 44 80 18 81 58 82 5.3 83 10 84 3.1 85 79 88 10 89 15 93 7.6 95 91 964.7 97 11 99 29 100 21 102 115 104 0.9 106 2.0 108 21 110 7.4 112 14 11325 115 97 117 54 119 92 121 15 122 57 123 21 124 13 125 62 126 52 127195 128 40 129 15 130 94 131 109 132 3.8 133 4.3 134 695 135 136 136 31137 3.1 138 11 139 12 140 81 141 16 142 17 143 131 144 54 145 91 146 70147 870 148 287 149 3.9 150 48 151 2.2 152 95 154 2.3 155 6.2 156 23 157339 158 301 159 32 160 38 161 105 162 71 163 166 164 563 165 21 166 12167 83 168 133 169 55 170 2.9 171 7.1 172 15 173 78 174 35 175 4.4 17621 177 30 178 601 179 2.1 180 6.9 181 1.0 182 4.0 183 7.7 184 1.1 1851.2 186 4.3 187 128 188 155 189 1.7 190 148 191 4.6 192 8.8 193 3.9 1941.3 195 6.0 196 2.2 197 4.6 198 11 199 3.9 200 5.4 201 0.6 202 1.4 2031.5 204 3.1 205 31 206 21 207 11 208 9.6 209 1.0 210 0.8 211 987 212 75213 116 214 8.1 215 8.2 216 66 217 239 218 21 219 2.6 220 5.0 221 1.7222 1.6 223 3.5 224 5.9 225 2.8 226 9.2 227 5.6 228 7.2 229 44 230 44231 6.9 232 10 233 0.9 234 5.0 235 1.6 236 522 237 12 238 103 239 14 24018 241 8.5 242 102. In Vivo TRPM8 Antagonistic Assay in RatsTest Compound:

The compounds of Examples were used in TRPM8 antagonistic assay in rats.

Method:

The antagonistic activity of compounds was assessed in the “wet-dog”shakes (WDS) model in rats. Rats exhibit shaking behavior in response tomenthol, a TRPM8 agonist. Pretreatment of the rats with a TRPM8antagonist prior to menthol administration inhibits the observed shakingbehavior.

To assess the ability of a TRPM8 antagonist to prevent menthol inducedshaking behavior in Sprague Dawley (SD) male rats, test compounds (3mg/kg, po, in 0.5% methyl cellulose; N=3-4/group) were administered 1hour prior to menthol challenge (50 mg/kg, ip, in 10% Macrogol 15Hydroxystearate/saline). Spontaneous WDS were counted for 5 min postmenthol dosing. Inhibition of the spontaneous WDS behavior relative tovehicle pretreatment is expressed as percent inhibition, calculated asfollows: % Inhibition=[1−(treatment WDS count/vehicle WDS count)]×100.

Results:

The following Table 20 shows a percent inhibition at 3 mg/kg of eachtest compound.

TABLE 20 Test Compound TRPM8 antagonistic assay (Example No.) (%Inhibition @ 3 mg/kg) 10 74.8% 106 92.7% 149 98.8% 184 67.0% 185 93.8%186 83.5% 210 83.3% 227 72.5%

INDUSTRIAL APPLICABILITY

The compound (I) of the present invention is useful for the preventionand treatment of various diseases involving TRPM8 (e.g., chronic painsuch as neuropathic pain (preferably, neuropathic pain caused by coldallodynia or diabetic neuropathy)).

The invention claimed is:
 1. A compound of the general formula (I):

wherein Ring A is bicyclic aromatic heterocycle comprised of (a)pyridine condensed with benzene; or (b) pyridine condensed withmonocyclic aromatic heterocycle, and Ring A binds to a sulfonylaminomoiety on a carbon atom adjacent to a nitrogen atom of pyridine ringconstituting Ring A, Ring B is (a) monocyclic or bicyclic aromatichydrocarbon; (b) monocyclic or bicyclic alicyclic hydrocarbon; (c)monocyclic or bicyclic aromatic heterocycle; or (d) monocyclic orbicyclic non-aromatic heterocycle, Ring C is (a) benzene; or (b)monocyclic aromatic heterocycle, R¹ is (a) hydrogen; (b) optionallysubstituted alkyl; (c) optionally substituted cycloalkyl; (d) optionallysubstituted alkoxy; (e) optionally substituted phenyl; (f) halogen; or(g) nitrile, R^(2a), R^(2b), R^(2c) and R^(2d) are each independently(a) hydrogen; (b) optionally substituted alkyl; (c) optionallysubstituted cycloalkyl; (d) optionally substituted alkoxy; (e)optionally substituted phenyl; (f) optionally substituted monocyclicaromatic heterocyclic group; (g) optionally substituted monocyclicnon-aromatic heterocyclic group; (h) halogen; or (i) nitrile, R^(3a),R^(3b), R^(3c) and R^(3d) are each independently (a) hydrogen; (b)optionally substituted alkyl; (c) optionally substituted cycloalkyl; (d)optionally substituted alkoxy; (e) optionally substituted cycloalkoxy;(f) optionally substituted phenyl; (g) optionally substituted monocyclicaromatic heterocyclic group; (h) optionally substituted monocyclicnon-aromatic heterocyclic group; (i) optionally substituted phenoxy; (j)halogen; or (k) hydroxy, or two substituent groups selected from R^(3a),R^(3b), R^(3c) and R^(3d) combine each other to form oxo, R⁵ and R⁶ areeach independently (a) hydrogen; (b) alkyl; (c) halogenoalkyl; (d)cycloalkyl; or (e) halogenocycloalkyl, or R⁵ and R⁶ combine each otherat their terminals together with the adjacent carbon atom to formmonocyclic alicyclic hydrocarbon, n is 0, 1 or 2; X is carboxy,alkoxycarbonyl, hydroxyalkyl, optionally substituted aminocarbonyl, oroptionally substituted alkanoyl; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R¹ is (a) hydrogen; (b)C₁-C₆ alkyl which may be optionally substituted by 1 to 7 groupsselected from C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen, oxo and hydroxy;(c) C₃-C₇ cycloalkyl which may be optionally substituted by 1 to 7groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; (d) C₁-C₆alkoxy which may be optionally substituted by 1 to 7 groups selectedfrom C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen and hydroxy; (e) phenylwhich may be optionally substituted by 1 to 3 groups selected from C₁-C₆alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl,C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (f) halogen; or (g)nitrile, R^(2a), R^(2b), R^(2c) and R^(2d) are each independently (a)hydrogen; (b) C₁-C₆ alkyl which may be optionally substituted by 1 to 7groups selected from C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, halogen, oxo andhydroxy; (c) C₃-C₇ cycloalkyl which may be optionally substituted by 1to 7 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 groupsselected from C₁-C₆ alkoxy, C₃-C₇ cycloalkyl and halogen; (e) phenylwhich may be optionally substituted by 1 to 3 groups selected from C₁-C₆alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl,C_(i)-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (f) 5 to 6-memberedmonocyclic aromatic heterocyclic group which may be optionallysubstituted by 1 to 3 groups selected from C₁-C₆ alkyl. C₁-C₆halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy,C₁-C₆ halogenoalkoxy and halogen; (g) 4 to 7-membered monocyclicnon-aromatic heterocyclic group which may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxyand halogen; (h) halogen; or (i) nitrile, R^(3a), R^(3b), R^(3c) andR^(3d) are each independently (a) hydrogen; (b) C₁-C₆ alkyl which may beoptionally substituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl,C₃-C₇ halogenocycloalkyl (in which the cycloalkyl and halogenocycloalkylmay be each independently optionally substituted by 1 to 3 groupsselected from C₁-C₆ alkyl and C₁-C ₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆halogenoalkoxy, phenyl, 5 to 6-membered monocyclic aromatic heterocyclicgroup, 4 to 7-membered monocyclic non-aromatic heterocyclic group (inwhich the phenyl, aromatic heterocyclic group and non-aromaticheterocyclic group may be each independently optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxyand halogen), halogen, oxo and hydroxy; (c) C₃-C₇ cycloalkyl which maybe optionally substituted by 1 to 7 groups selected from C₁-C₆ alkyl,C₁-C₆ halogenoalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, halogen andhydroxy; (d) C₁-C₆ alkoxy which may be optionally substituted by 1 to 7groups selected from C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl (inwhich the cycloalkyl and halogenocycloalkyl may be each independentlyoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl andC₁-C₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, phenyl, 5 to6-membered monocyclic aromatic heterocyclic group, 4 to 7-memberedmonocyclic non-aromatic heterocyclic group (in which the phenyl,aromatic heterocyclic group and non-aromatic heterocyclic group may beeach independently optionally substituted by 1 to 3 groups selected fromC₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen),halogen and hydroxy; (e) C₃-C₇ cycloalkoxy which may be optionallysubstituted by 1 to 7 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, halogen and hydroxy;(f) phenyl which may be optionally substituted by 1 to 3 groups selectedfrom C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy and halogen; (g)5 to 6-membered monocyclic aromatic heterocyclic group which may beoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆halogenoalkyl, C₃-C₇ cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy,C₁-C₆ halogenoalkoxy and halogen; (h) 4 to 7-membered monocyclicnon-aromatic heterocyclic group which may be optionally substituted by 1to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇cycloalkyl, C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxyand halogen; (i) phenoxy which may be optionally substituted by 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, C₃-C₇ cycloalkyl,C₃-C₇ halogenocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy andhalogen; (j) halogen; or (k) hydroxy, or two substituent groups selectedfrom R^(3a), R^(3b), R^(3c) and R^(3d) combine each other to form oxo,R⁵ and R⁶ are each independently (a) hydrogen; (b) C₁-C₆ alkyl; (c)C₁-C₆ halogenoalkyl; (d) C₃-C₇ cycloalkyl; or (e) C₃-C₇halogenocycloalkyl, or R⁵ and R⁵ combine each other at their terminalstogether with the adjacent carbon atom to form 3 to 7-memberedmonocyclic alicyclic hydrocarbon, X is (a) carboxy; (b) C₁-C₆alkoxycarbonyl; (c) hydroxy-C₁-C₆ alkyl; (d) aminocarbonyl wherein anitrogen atom may be optionally substituted by one group selected fromC₁-C₆ alkyl, C₁-C₆ alkoxy and nitrite; or (e) C₂-C₇ alkanoyl which maybe optionally substituted by 1 to 3 halogens, or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 2, wherein Ring A isquinoline, isoquinoline or pyrrolopyridine, or a pharmaceuticallyacceptable salt thereof.
 4. The compound of claim 2, wherein Ring A, R¹,R^(2a), R^(2b), R^(2c) and R^(2d) combine each other to form a group ofthe following formula:

wherein one of Y and Z is CR^(2d), and the other is a chemical bond, ora pharmaceutically acceptable salt thereof.
 5. The compound of claim 4,wherein Ring C is benzene, and X is carboxy and binds to Ring C at4-position to the aminosulfonyl moiety, or a pharmaceutically acceptablesalt thereof.
 6. The compound of claim 5, wherein Ring B is (a)monocyclic or bicyclic aromatic hydrocarbon; or (b) monocyclic orbicyclic aromatic heterocycle, and n is 0 or 1, or a pharmaceuticallyacceptable salt thereof.
 7. The compound of claim 6, wherein a partialstructure:

is a group of the following formula (A):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim6, wherein a partial structure:

is a group of the following formula (B):

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim7 wherein R¹ is (a) C₁-C₆ alkyl which may be optionally substituted by 1to 7 halogens; (b) C₃-C₇ cycloalkyl; (c) alkoxy; or (d) halogen, R^(2b)and R^(2b) are hydrogen, R^(2b) is (a) hydrogen; (b) C₁-C₆ alkyl whichmay be optionally substituted by 1 to 7 halogens; (c) C₃-C₇ cycloalkyl;or (d) C₁-C₆ alkoxy, R^(3a) and R^(3b) are each independently (a)hydrogen; (b) C₁-C₆ alkyl which may be optionally substituted by 1 to 7groups selected from C₃-C₇ cycloalkyl (in which the cycloalkyl may beoptionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl andC₁-C₆ halogenoalkyl), C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, and halogen;(c) C₃-C₇ cycloalkyl which may be optionally substituted by 1 to 7groups selected from C₁-C₆ alkyl, C₁-C₆ halogenoalkyl, and halogen; (d)C₁-C₆ alkoxy which may be optionally substituted by 1 to 7 groupsselected from C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ halogenoalkoxy, andhalogen; or (e) halogen, R^(3c) and R^(3d) are hydrogen, R⁵ and R⁶ arehydrogen, n is 1, or a pharmaceutically acceptable salt thereof.
 10. Thecompound of claim 1, which is selected from he group consisting of4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid;4-{[[3-fluoro-4-(trifluoromethoxy)benzyl](4-methylisoquinolin-3-yDamino]sulfonyl}benzoicacid;4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoicacid;4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-(3-methylquinolin-2-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid;4-{[[4-fluoro-3-(trifluoromethyl)benzyl](3-methylisoquinolin-2-amino]sulfonyl}benzoicacid; 4-{[(4-t-butylbenzyl)(4-methylisoquinolin-3-amino]sulfony}benzoicacid;4-{[[4-(cyclopropylmethyl)benzyl}(4-methylisoquinolin-3-amino}sulfonyl}benzoicacid;4-{[[R4-fluoro-3-(trifluoromethyl)benzyly]4-methylisoquinolin-3-y0amino]sulfonyl}benzoicacid;4-{[(4-methylisoquinolin-3-yl))2-naphthylmethy)amino]sulfony}benzoicacid;4-({(1-methoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzy]amino}sulfony)-benzoicacid:4-({(4-chloroisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid;4-([(4-methylisoquinolin-3-yl)(5,6,7,8-tetrahydronaphthalen-2-ylmethy)amino]sulfonyl}-benzoic acid;4-{[(2,3-dihydro-1H-inden-5-yl)methyl)(4-methylisoquinolin-3-yl)amino]sulfony}benzoicacid:4-{[[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)methyl](4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-{[[(2,2-dimethyl-2,3-dihydro-1H-inden-5-yl)mthyl]4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-{[[(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid;4-{[[(1-benzothiophen-2-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid;4-({(1,4-dimethylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoicacid; and4-({(4-methylisoquinolin-3-yl)[4-(2,2,2-trifluoro-1-methoxy-1-methylethyl)benzyl]amino}-sulfonylbenzoic acid; or a pharmaceutically acceptable salt thereof.
 11. Thecompound of claim 1, which is selected from the group consisting of4-({(1-cyclopropyl-4-methylisoquino-y)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoic acid;4-({(1-methoxy-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoicacid;4-({(1-isopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzoicacid;4-{[{3-chloro-44cyclopropyl(difluoro)methyl]benzyl}(4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid;4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(1-cyclopropyl-4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid;4-{[{44cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-methylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoicacid;4-R(4-cyclopropylisoquinolin-3-yl){[5-(trifluoromethyl)pyridin-2-yl]methyl}amino)sulfonyl]-benzoicacid;4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(4-cyclopropylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid;4-{[{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-cyclopropylisoquinolin-3-yl)amino]-sulfonyl}benzoicacid; 4-({(4-cyclopropylisoquinolin-3-yl)[5-(trifluoromethoxy)-2,3-dihydro-1 H-inden-1-yl]amino}sulfonyl)benzoic acid;4-({{3-chloro-4-[cyclopropyl(difluoro)methypenzyl}[4-(trifluoromethyl)isoquinolin-3-yl]-amino}sulfonyl)benzoicacid; and4-({{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}[4-(trifluoromethyl)isoquinolin-3-yl]-amino}sulfonyl)benzoicacid; or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition, comprising as the active ingredient thecompound of claim 1 or a pharmaceutically acceptable salt thereof. 13.The compound of claim 9, wherein Ring B is benzene or pyridine, R¹ ismethyl, trifluoromethyl, isopropyl, cyclopropyl, or methoxy, R^(3a) andR^(3b) are each independently (a) hydrogen; (b) C₁-C₆ alkyl which may beoptionally substituted by 1 to 7 groups selected from C₃-C₇ cycloalkyl(in which the cycloalkyl may be optionally substituted by 1 to 3 groupsselected from C₁-C₆ alkyl and C₁-C₆ halogenoalkyl), C_(i)-C₆alkoxy,C₁-C₆ halogenoalkoxy, and halogen; (c) C₃-C₇ cycloalkyl; (d) C₁-C₆alkoxywhich may be optionally substituted by 1 to 7 halogens; or (e) halogen,or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, which is4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzy]amino}sulfonyl)benzoicacid or a pharmaceutically acceptable salt thereof.
 15. The compound ofclaim 1, which is4-({(1-isopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl}amino}sulfonyl)benzoicacid or a pharmaceutically acceptable salt thereof.
 16. The compound ofclaim 1, which is4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid or a pharmaceutically acceptable salt thereof.
 17. The compound ofclaim 1, which is4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid or a pharmaceutically acceptable salt thereof.
 18. Thecompound of claim 1, which is4-{[{3-chloro-4-[cyclopropyl(difluoro)methyl]benzyl}(1-cyclopropyl-4-methylisoquinolin-3-yl)amino}-sulfonyl}benzoicacid or a pharmaceutically acceptable salt thereof.
 19. The compound ofclaim 1, which is4-{[{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoicacid or a pharmaceutically acceptable salt thereof.
 20. The compound ofclaim 1, which is4-({[4-(trifluoromethoxy)benzyl][4-(trifluoromethyl)isoquinolin-3-yl]amino}sulfonyl)benzoicacid or a pharmaceutically acceptable salt thereof.
 21. The compound ofclaim 1, which is4-[((4-cyclopropylisoquinolin-3-yl){[5-(trifluoromethyl)pyridin-2-yl]methyl}amino)sulfonyl]benzoicacid or a pharmaceutically acceptable salt thereof.
 22. The compound ofclaim 1, which is4-{[{4-[cyclopropyl(difluoro)methyl]-3-fluorobenzyl}(4-cyclopropylisoquinolin-3-yl)amino]sulfonyl}benzoicacid or a pharmaceutically acceptable salt thereof.
 23. A method fortreating a disease or condition selected from chronic pain, cephalalgia,urologic disease, carcinoma, respiratory disease, gastrointestinaldisease, psychiatric disease, neurological disease, and dermatosis, themethod comprising administering to a subject an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof. 24.The method of claim 23, wherein the disease or condition is selectedfrom chronic pain and urologic disease.
 25. The method of claim 24,wherein the disease or condition is selected from neuropathic pain,nociceptive pain, and mixed pain.